Substituted pyrazolo[4,3-e]diazepines, pharmaceutical compositions containing them, use as medicinal products and processes for preparing them

ABSTRACT

The invention relates to novel substituted pyrazolo[4,3-e]-diazepines of general formula: 
                 
 
to pharmaceutical compositions containing them, to their use as medicinal products and to processes for preparing them.

This application is a nonprovisional application for patent filed under35 U.S.C. §371, which is a nationalization of PCT InternationalApplication number PCT/EP00/13380 filed Dec. 27, 2000, which claimsbenefit of priority from U.S. provisional application No. 60/209,339filed Jun. 5, 2000, and French patent application number 00/00095 filedJan. 5, 2000.

The invention relates to novel substituted pyrazolo-[4,3]diazepins, topharmaceautical compositions containing them, to their use as medicalproducts and to processes for preparing them.

TECHNOLOGICAL BACKGROUND OF THE INVENTION

Cyclic adenosine 3′,5′-monophosphate (cAMP) is a ubiquitousintracellular second messenger, which is intermediate between a firstmessenger (hormone, neurotransmitter or autacoid) and the cellularfunctional responses: the first messenger stimulates the enzymeresponsible for the synthesis of cAMP; depending on the cells concerned,the cAMP then intervenes in a great number of functions: metabolic,contractile or secretory.

The effects of cAMP end when it is degraded by cyclic nucleotidephosphodiesterases, which are intracellular enzymes that catalyse itshydrolysis into inactive adenosine 5′-monophosphate.

At least 11 major families of cyclic nucleotide phosphodiesterases (PDE)have been distinguished in mammals, numbered from 1 to 11 according totheir structure, their kinetic behaviour, their substrate specificity ortheir sensitivity to effectors (Beavo J. A. et al. (1990) TrendsPharmacol. Sci. 11, 150-155. Beavo J. A. et al. (1994) MolecularPharmacol. 46, 399-405). The PDE4 enzymes are specific for cAMP.

Non-specific phosphodiesterase inhibitor compounds are known, whichinhibit several families of enzymes. This is the case for certain methylxanthines such as theophylline. These compounds have a low therapeuticindex, in particular on account of their action on types of PDE presentin cells other than the target cells. Conversely, certain families ofPDE can be selectively inhibited by various pharmacological agents: thehydrolysis of cyclic nucleotides is slowed down and their concentrationthus increases in only the cells in which the type of PDE that issensitive to the inhibitor is found.

A specific advantage is shown for the phosphodiesterases 4 (PDE4), whichhave been identified in many tissues including the central nervoussystem, the heart, vascular endothelium, vascular smooth muscle and thatof the aerial pathways, myeloid lines and lymphoid lines.

An increase in cAMP in the cells involved in inflammation inhibits theiractivation: inhibition of the synthesis and release of mediators inmastocytes, monocytes, polymorphonuclear eosinophils and basophils,inhibition of chemotaxis and degranulation of polymorphonuclearneutrophils and eosinophils, inhibition of the proliferation anddifferentiation of lymphocytes.

Cytokines, in particular TNF and interleukins, produced by various typesof leukocytes such as the T lymphocytes, monocytes and polymorphonucleareosinophils, play an important role in triggering inflammatorymanifestations, in particular in response to stimulation by an allergenin the respiratory pathways.

Moreover, cAMP reduces the tonus of the smooth muscle fibres in theaerial pathways.

It might thus be expected that selective PDE4 inhibitors would havetherapeutic activity as anti-inflammatory and anti-allergic medicinalproducts, and in the treatment of various respiratory diseases such asasthma, emphysema and chronic bronchitis.

Extensive research has been conducted for several years into theproduction and development of powerful PDE4 inhibitors. This is found tobe difficult due to the fact that many potential PDE4 inhibitors are notdevoid of activity on the phosphodiesterases of other families.

At the present time, the lack of selectivity of PDE4 inhibitors thusrepresents a major problem, given the extent of the functions regulatedby cAMP. There is thus a need for powerful and selective PDE4inhibitors, i.e. inhibitors which have no action with respect to PDEsbelonging to other families and particularly PDEs which regulate cGMP.

SUMMARY OF THE INVENTION

The invention relates to substituted pyrazolo[4,3-e]-diazepines ofgeneral formula I below:

in which:

-   -   R1 is chosen from the following groups:        -   hydrogen;        -   linear or branched alkyl containing from 1 to 6 carbon            atoms;        -   cycloalkyl containing from 3 to 6 carbon atoms;        -   alkylcycloalkyl comprising an alkyl group containing from 1            to 6 carbon atoms and a cycloalkyl group containing from 3            to 6 carbon atoms;        -   aryl containing from 5 to 10 carbon atoms, optionally            interrupted with a hetero atom chosen from nitrogen, oxygen            and sulphur;        -   arylalkyl containing from 6 to 10 carbon atoms, optionally            interrupted with a hetero atom chosen from nitrogen, oxygen            and sulphur;        -   alkylaryl containing from 6 to 10 carbon atoms, optionally            interrupted with a hetero atom chosen from nitrogen, oxygen            and sulphur;        -   linear or branched alkenyl containing from 2 to 6 carbon            atoms;        -   the groups (CH₂)_(n)OR_(B), (CH₂)_(n)CF₃,            (CH₂)_(n)C(O)R_(B), (CH₂)_(n)COOR_(B), (CH₂)_(n)OC(O)R_(A),            (CH₂)_(n)SR_(B), (CH₂)_(n)C(S)R_(B), (CH₂)_(n)C(S)OR_(B),            (CH₂)_(n)C(S)SR_(B), (CH₂)_(n)NR_(B)R_(C),            (CH₂)_(n)C(O)NR_(B)R_(C), (CH₂)_(n)NR_(C)C(O)R_(B),            (CH₂)_(n)NR_(D)C(O)NR_(D)R_(B) or (CH₂)_(n)Z, in which,            -   R_(A) is chosen from linear or branched alkyl containing                from 1 to 6 carbon atoms;            -   cycloalkyl containing from 3 to 6 carbon atoms;            -   alkylcycloalkyl comprising an alkyl group containing                from 1 to 6 carbon atoms and a cycloalkyl group                containing from 3 to 6 carbon atoms;            -   aryl containing from 5 to 10 carbon atoms, optionally                interrupted with a hetero atom chosen from nitrogen,                oxygen and sulphur;            -   arylalkyl containing from 6 to 10 carbon atoms,                optionally interrupted with a hetero atom chosen from                nitrogen, oxygen and sulphur;            -   alkylaryl containing from 6 to 10 carbon atoms,                optionally interrupted with a hetero atom chosen from                nitrogen, oxygen and sulphur;            -   linear or branched alkenyl containing from 2 to 6 carbon                atoms;            -   R_(B) and R_(C), which may be identical or different,                are chosen from: hydrogen;            -   linear or branched alkyl containing from 1 to 6 carbon                atoms;            -   cycloalkyl containing from 3 to 6 carbon atoms;            -   alkylcycloalkyl comprising an alkyl group containing                from 1 to 6 carbon atoms and a cycloalkyl group                containing from 3 to 6 carbon atoms;            -   aryl containing from 5 to 10 carbon atoms, optionally                interrupted with a hetero atom chosen from nitrogen,                oxygen and sulphur;            -   arylalkyl containing from 6 to 10 carbon atoms,                optionally interrupted with a hetero atom chosen from                nitrogen, oxygen and sulphur;            -   alkylaryl containing from 6 to 10 carbon atoms,                optionally interrupted with a hetero atom chosen from                nitrogen, oxygen and sulphur;            -   linear or branched alkenyl containing from 2 to 6 carbon                atoms, it being possible for R_(B) and R_(C) to form a                ring containing from 5 to 7 atoms which can include one                or more hetero atoms chosen from S, N and O;            -   R_(D) is hydrogen or linear or branched alkyl containing                from 1 to 6 carbon atoms;            -   Z is a halogen; and            -   n is an integer from 0 to 4 inclusive;    -   R2 is chosen from the following groups:        -   linear or branched alkyl containing from 1 to 6 carbon            atoms;        -   alkylcycloalkyl comprising an alkyl group containing from 1            to 6 carbon atoms and a cycloalkyl group containing from 3            to 6 carbon atoms;        -   cycloalkyl containing from 3 to 6 carbon atoms; aryl            containing from 5 to 10 carbon atoms, optionally interrupted            with a hetero atom chosen from nitrogen, oxygen and sulphur;        -   alkylaryl containing from 6 to 10 carbon atoms, optionally            interrupted with a hetero atom chosen from nitrogen, oxygen            and sulphur;        -   linear or branched alkenyl containing from 2 to 6 carbon            atoms;        -   the groups (CH₂)_(m)OR_(B), (CH₂)_(n)CF₃,            (CH₂)_(m)C(O)R_(B), (CH₂)_(m)COOR_(B), (CH₂)_(m)OC(O)R_(A),            (CH₂)_(m)SR_(B), (CH₂)_(m)C(S)R_(B), (CH₂)_(m)C(S)OR_(B),            (CH₂)_(m)C(S)SR_(B), (CH₂)_(m)NR_(B)R_(C),            (CH₂)_(m)C(O)NR_(B)R_(C), (CH₂)_(m)NR_(C)C(O)R_(B),            (CH₂)_(m)NR_(D)C(O)NR_(D)R_(B) or (CH₂)_(m)Z, in which,            -   R_(A), R_(B), R_(C) R_(D) and Z are as defined above,                and            -   m is an integer from 1 to 4 inclusive;            -   n is an integer from 0 to 4 inclusive;    -   R3 is chosen from the following groups:        -   hydrogen;        -   linear or branched alkyl containing from 1 to 6 carbon            atoms;        -   cycloalkyl containing from 3 to 6 carbon atoms;        -   alkylcycloalkyl comprising an alkyl group containing from 1            to 6 carbon atoms and a cycloalkyl group containing from 3            to 6 carbon atoms;        -   aryl containing from 5 to 10 carbon atoms, optionally            interrupted with a hetero atom chosen from nitrogen, oxygen            and sulphur;        -   arylalkyl containing from 6 to 10 carbon atoms, optionally            interrupted with a hetero atom chosen from nitrogen, oxygen            and sulphur;        -   alkylaryl containing from 6 to 10 carbon atoms, optionally            interrupted with a hetero atom chosen from nitrogen, oxygen            and sulphur;        -   linear or branched alkenyl containing from 2 to 6 carbon            atoms;        -   the groups (CH₂)_(n)OR_(B), (CH₂)_(n)CF₃,            (CH₂)_(n)C(O)R_(B), (CH₂)_(n)COOR_(B), (CH₂)_(n)OC(O)R_(A),            (CH₂)_(n)SR_(B), (CH₂)_(n)C(S)R_(B), (CH₂)_(n)C(S)OR_(B),            (CH₂)_(n)C(S)SR_(B), (CH₂)_(n)NR_(B)R_(C),            (CH₂)_(n)C(O)NR_(B)R_(C), (CH₂)_(n)NR_(C)C(O)R_(B),            (CH₂)_(n)NR_(D)C(O)NR_(D)R_(B) or (CH₂)_(n)Z, in which,            -   R_(A), R_(B), R_(C) R_(D) and n are as defined above;        -   the aryl, arylalkyl and alkylaryl groups defined above being            unsubstituted or substituted on the aryl group with 1, 2 or            3 groups chosen from:            -   halogen, hydroxyl, NO, NO₂, CN, alkoxy containing from 1                to 4 carbon atoms, (CH₂)_(n)OR_(B),                (CH₂)_(n)NR_(B)R_(C), (CH₂)_(n)NC(O)R_(B),                (CH₂)_(n)HNSO₂R_(B), (CH₂)_(n)N (SO₂R_(B))₂, CO₂R_(B),                CF₃ and            -   in which R_(B), R_(C) and n are as defined above; and        -   the dotted line present in formula I indicates that the bond            between W and the carbon in position 5 may be:            -   a single bond, in which case W represents a nitrogen                atom substituted with a hydrogen atom,            -   a double bond, and in this case W represents an                unsubstituted nitrogen atom;        -   X is S, O, N—CN or N—R_(B) in which R_(B) is as defined            above;            as well as the oxides, the tautomeric forms and the            corresponding optical isomers or the pharmaceutically            acceptable derivatives of the compounds of formula I, with            the proviso that when    -   R1 represents a methyl group, R2 an ethyl group, W is N, X is an        oxygen atom and the bond between W and the carbon in position 5        is a double bond, then        -   R3 is neither an unsubstituted phenyl group nor a phenyl            group bearing a fluorine atom in an ortho position as sole            substituent.

The compounds of the invention have inhibitory properties on PDE4 and/orTNFα-release. Some of these compounds are also selective inhibitors ofPDE4 subtypes. The compounds of the invention can be used in thetreatment of complaints including cancer, acquired immunodeficiencysyndrome, fibrosis, excessive scarring including excessive dermalscarring such as normal or abnormal dermal scarring following woundingor surgery, osteoarthritis, osteoporosis, multiple sclerosis, anxiety,depression, atopic dermatitis, rheumatoid arthritis, septic shock,immune diseases including disseminated lupus erythematous, psoriasis,graft rejection and allergic rhinitis, as well as diseases involving theproduction of TNFα and more particularly in the treatment ofinflammatory complaints such as asthma, chronic obstructivebronchopneumopathy (COPD), post-ischaemic lesions, pulmonaryhypertension, congestive cardiac insufficiency, acute respiratorydistress syndrome, and chronic inflammatory diseases of the intestine(IBD) such as Crohn's disease and ulcerative colitis.

The invention also relates to a process for synthesizing a compound ofgeneral formula I, the said process being characterized in that itcomprises:

-   -   1)when, in formula I, X is O or S, W is N and the bond between W        and the carbon in position 5, symbolized by ═, is a double bond:        -   the cyclization of a compound of general formula (C)            in which R1, R2, R3 and X have the meaning given above, to            give a synthetic intermediate or a final compound of general            formula D,    -   in which R1, R2, R3 and X have the meanings given above;    -   2) when, in formula I, X is S, W is N and the bond between W and        the carbon in position 5, symbolized by ═, is a double bond:        -   the thionation of a compound of general formula (D), in            which R1, R2 and R3 have the meaning given above and X is O,            to give a compound of formula I in which the bond between W            and the carbon atom in position 5 is a double bond, W is N            and X is sulphur;    -   3) when, in formula I, X is N—CN, W is N and the bond between W        and the carbon in position 5, symbolized by ═, is a double bond:        -   the reaction of a compound of general formula (G)            in which R1, R2 and R3 have the meaning given above, with a            compound of formula H₂N—CN, to give a compound of general            formula F below:    -   4) when, in formula I, X is N—R_(B), W is N and the bond between        W and the carbon in position 5, symbolized by ═, is a double        bond:        -   the reaction of a compound of general formula (G)            in which R1, R2 and R3 are as defined above, with a compound            of formula H₂N—R_(B), in which R_(B) is as defined above,    -   to give a compound of formula I in which the bond between W and        the carbon atom in position 5 is a double bond, W is N and X is        N—R_(B) (J. Med. Chem.; 42; 1999; 2909-2919).    -   5) when, in formula I, W is NH and the bond between W and the        carbon in position 5 is a single bond        -   the reaction of a compound of general formula            in which R1, R2, R3 and X are as defined above, with a            reducing agent, to give a compound of formula I in which W            is NH and the bond between W and the carbon in position 5 is            a single bond.

The invention also relates to a pharmaceutical composition comprising atleast one compound of general formula I as defined above, in combinationwith a pharmaceutically acceptable support.

The invention also relates to the use of a substitutedpyrazolo[4,3-e]diazepine of general formula I as a medicinal product.

The invention also relates to the use of a substitutedpyrazolo[4,3-e]diazepine of general formula I to prepare a medicinalproduct for treating complaints relating to a therapy with aphosphodiesterase 4 inhibitor.

The invention also relates to a method for treating a disease or acomplaint relating to a therapy with a phosphodiesterase 4 inhibitor,the said method comprising the administration of an effectiveconcentration of a compound of formula I to a patient.

The invention also relates to the use of a substitutedpyrazolo[4,3-e]diazepine of general formula I for the preparation of amedicinal product intended for treating mammals and particularly fortreating humans, especially a medicinal product intended for treatingconditions including cancer, acquired immunodeficiency syndrome,fibrosis, excessive scarring including excessive dermal scarring such asnormal or abnormal dermal scarring following wounding or surgery,osteoarthritis, osteoporosis, multiple sclerosis, anxiety, depression,atopic dermatitis, rheumatoid arthritis, septic shock, immune diseasesincluding disseminated lupus erythematous, psoriasis, graft rejection,allergic rhinitis, diseases involving the production of TNFα and moreparticularly inflammatory complaints such as asthma, chronic obstructivebronchopneumopathy (COPD), post-ischaemic lesions, pulmonaryhypertension, congestive cardiac insufficiency, acute respiratorydistress syndrome, and chronic inflammatory diseases of the intestine(IBD) such as Crohn's disease and ulcerative colitis.

DETAILED DESCRIPTION OF THE INVENTION

The present invention thus relates to the compounds of general formulaI:

in which the dotted line, X, W, R1, R2 and R3 are as defined above.

The compounds of formula I above in which W represents an unsubstitutednitrogen atom and the bond between W and the carbon in position 5,symbolized by ═, is a double bond, are preferred.

Among the compounds of general formula I that are thus preferred are thecompounds corresponding to the general formula II:

in which:

-   -   R1 is a linear or branched alkyl group containing from 1 to 6        carbon atoms;    -   a cycloalkyl group containing from 3 to 6 carbon atoms;    -   an alkylcycloalkyl group comprising an alkyl group containing        from 1 to 6 carbon atoms and a cycloalkyl group containing from        3 to 6 carbon atoms;    -   an aryl group containing from 5 to 10 carbon atoms, optionally        interrupted with a hetero atom chosen from nitrogen, oxygen and        sulphur;    -   an arylalkyl group containing from 6 to 10 carbon atoms,        optionally interrupted with a hetero atom chosen from nitrogen,        oxygen and sulphur;    -   an alkylaryl group containing from 6 to 10 carbon atoms,        optionally interrupted with a hetero atom chosen from nitrogen,        oxygen and sulphur;    -   a linear or branched alkenyl group containing from 2 to 6 carbon        atoms;    -   the groups (CH₂)_(n)OR_(B), (CH₂)_(n)CF₃, (CH₂)_(n)C(O)R_(B),        (CH₂)_(n)COOR_(B), (CH₂)_(n)OC(O)R_(A), (CH₂)_(n)SR_(B),        (CH₂)_(n)NR_(B)R_(C), (CH₂)_(n)C(O)NR_(B)R_(C),        (CH₂)_(n)NR_(C)C(O)R_(B) or (CH₂)_(n)Z, in which        -   R_(A) is chosen from linear or branched alkyl containing            from 1 to 6 carbon atoms;        -   cycloalkyl containing from 3 to 6 carbon atoms;        -   alkylcycloalkyl comprising an alkyl group containing from 1            to 6 carbon atoms and a cycloalkyl group containing from 3            to 6 carbon atoms;        -   aryl containing from 5 to 10 carbon atoms, optionally            interrupted with a hetero atom chosen from nitrogen, oxygen            and sulphur;        -   arylalkyl containing from 6 to 10 carbon atoms, optionally            interrupted with a hetero atom chosen from nitrogen, oxygen            and sulphur;        -   alkylaryl containing from 6 to 10 carbon atoms, optionally            interrupted with a hetero atom chosen from nitrogen, oxygen            and sulphur;        -   linear or branched alkenyl containing from 2 to 6 carbon            atoms;        -   R_(B) and R_(C), which may be identical or different, are            chosen from: hydrogen;        -   linear or branched alkyl containing from 1 to 6 carbon            atoms;        -   cycloalkyl containing from 3 to 6 carbon atoms;        -   alkylcycloalkyl comprising an alkyl group containing from 1            to 6 carbon atoms and a cycloalkyl group containing from 3            to 6 carbon atoms;        -   aryl containing from 5 to 10 carbon atoms, optionally            interrupted with a hetero atom chosen from nitrogen, oxygen            and sulphur;        -   arylalkyl containing from 6 to 10 carbon atoms, optionally            interrupted with a hetero atom chosen from nitrogen, oxygen            and sulphur;        -   alkylaryl containing from 6 to 10 carbon atoms, optionally            interrupted with a hetero atom chosen from nitrogen, oxygen            and sulphur;        -   linear or branched alkenyl containing from 2 to 6 carbon            atoms;        -   R_(B) and R_(C) possibly forming a ring containing from 5 to            7 atoms which may include one or more hetero atoms chosen            from S, N or O;        -   Z is a halogen; and        -   n is an integer from 0 to 4 inclusive;    -   R2 is a linear or branched alkyl group containing from 1 to 4        carbon atoms;    -   (CH₂)_(n)CF₃, in which n is an integer from 0 to 4 inclusive;    -   methylcyclopropyl;    -   linear or branched alkenyl containing from 2 to 6 carbon atoms;    -   or a group (CH₂)_(m)OR_(B) and (CH₂)_(m)CO₂R_(B), in which m is        an integer from 1 to 3 inclusive and R_(B) is as described        above;    -   R3 is a linear or branched alkyl group containing from 1 to 6        carbon atoms;    -   a cycloalkyle group containing from 3 to 6 carbon atoms;    -   an alkylcycloalkyl group comprising an alkyl group containing        from 1 to 6 carbon atoms and a cycloalkyl group containing from        3 to 6 carbon atoms;    -   an aryl group containing from 5 to 10 carbon atoms, optionally        interrupted with a hetero atom chosen from nitrogen, oxygen and        sulphur;    -   an arylalkyl group containing from 6 to 10 carbon atoms,        optionally interrupted with a hetero atom chosen from nitrogen,        oxygen and sulphur;    -   an alkylaryl group containing from 6 to 10 carbon atoms,        optionally interrupted with a hetero atom chosen from nitrogen,        oxygen and sulphur;    -   an linear or branched alkenyl group containing from 2 to 6        carbon atoms;    -   the groups (CH₂)_(n)OR_(B), (CH₂)_(n)C(O)R_(B),        (CH₂)_(n)COOR_(B), (CH₂)_(n)OC(O)R_(A), (CH₂)_(n)NR_(B)R_(C),        (CH₂)_(n)C(O)NR_(B)R_(C) and (CH₂)_(n)NR_(C)C(O)R_(B), in which,        -   R_(A), R_(B), R_(C) and n are as defined above;    -   the aryl, arylalkyl and alkylaryl groups defined above being        unsubstituted or substituted on the aryl group with 1, 2 or 3        groups chosen from:        -   halogen, hydroxyl, NO, NO₂, CN, alkoxy containing from 1 to            4 carbon atoms, (CH₂)_(n)OR_(B), (CH₂)_(n)NR_(B)R_(C)            (CH₂)_(n)NC(O)R_(B), (CH₂)_(n)HNSO₂R_(B),            (CH₂)_(n)N(SO₂R_(B))₂, CO₂R_(B), CF₃ and            in which R_(B), R_(C) and n are as defined above; and,    -   X is O, S or NCN.

The invention relates particularly to the compounds of general formulaII in which:

-   -   R1 is a linear or branched alkyl group containing from 1 to 6        carbon atoms;    -   a cycloalkyl group containing from 3 to 6 carbon atoms;    -   an alkylcycloalkyl group comprising an alkyl group containing        from 1 to 6 carbon atoms and a cycloalkyl group containing from        3 to 6 carbon atoms;    -   an aryl group containing from 5 to 10 carbon atoms, optionally        interrupted with a hetero atom chosen from nitrogen, oxygen and        sulphur;    -   an alkylaryl group containing from 6 to 10 carbon atoms,        optionally interrupted with a hetero atom chosen from nitrogen,        oxygen and sulphur;    -   a linear or branched alkenyl group containing from 2 to 6 carbon        atoms;    -   the groups (CH₂)_(n)OR_(B), (CH₂)_(n)C(O)R_(B),        (CH₂)_(n)COOR_(B), (CH₂)_(n)OC(O)R_(A), (CH₂)_(n)NR_(B)R_(C),        (CH₂)_(n)C(O)NR_(B)R_(C), (CH₂)_(n)NR_(C)C(O)R_(B) or        (CH₂)_(n)Z, in which,        -   R_(A) is chosen from linear or branched alkyl containing            from 1 to 6 carbon atoms;        -   aryl containing from 5 to 10 carbon atoms, optionally            interrupted with a hetero atom chosen from nitrogen, oxygen            and sulphur;        -   alkylaryl containing from 6 to 10 carbon atoms, optionally            interrupted with a hetero atom chosen from nitrogen, oxygen            and sulphur;        -   R_(B) and R_(C), which may be identical or different, are            chosen from: hydrogen;        -   linear or branched alkyl containing, from 1 to 6 carbon            atoms;        -   aryl containing from 5 to 10 carbon atoms, optionally            interrupted with a hetero atom chosen from nitrogen, oxygen            and sulphur;        -   alkylaryl containing from 6 to 10 carbon atoms, optionally            interrupted with a hetero atom chosen from nitrogen, oxygen            and sulphur;        -   n is an integer from 0 to 4 inclusive;    -   R2 is a linear or branched alkyl group containing from 1 to 4        carbon atoms or a group (CH₂)_(m)OH or (CH₂)_(m)CO₂H, in which m        is an integer from 1 to 3 inclusive;    -   R3 is a linear or branched alkyl group containing from 1 to 6        carbon atoms;    -   a cycloalkyl group containing from 3 to 6 carbon atoms;    -   an aryl group containing from 5 to 10 carbon atoms, optionally        interrupted with a hetero atom chosen from nitrogen, oxygen and        sulphur;    -   an arylalkyl group containing from 6 to 10 carbon atoms,        optionally interrupted with a hetero atom chosen from nitrogen,        oxygen and sulphur;    -   an alkylaryl group containing from 6 to 10 carbon atoms,        optionally interrupted with a hetero atom chosen from nitrogen,        oxygen and sulphur;    -   the aryl, arylalkyl and alkylaryl groups defined above being        unsubstituted or substituted on the aryl group with 1, 2 or 3        groups chosen from:        -   halogen, hydroxyl, NO, NO₂, CN, alkoxy containing from 1 to            4 carbon atoms, (CH₂)_(n)OR_(B), (CH₂)_(n)NR_(B)R_(C)            (CH₂)_(n)NC(O)R_(B), CO₂R_(B), CF₃ and            in which R_(B), R_(C) and n are as defined above; and    -   X is O, S or NCN.

The invention relates more particularly to the compounds of generalformula II in which:

-   -   R1 is a linear or branched alkyl group containing from 1 to 4        carbon atoms;    -   a cycloalkyl group containing from 3 to 6 carbon atoms;    -   an alkylcycloalkyl group comprising an alkyl group containing        from 1 to 3 carbon atoms and a cycloalkyl group containing from        3 to 6 carbon atoms;    -   R2 is a linear or branched alkyl group containing from 1 to 4        carbon atoms;    -   R3 is a linear or branched alkyl group containing from 1 to 4        carbon atoms;    -   an aryl group containing from 5 to 10 carbon atoms, optionally        interrupted with a hetero atom chosen from nitrogen, oxygen and        sulphur, preferably phenyl or pyridyl, the aryl groups being        unsubstituted or substituted with 1, 2 or 3 groups, which may be        identical or different, chosen from NH₂, halogen, methoxy,        hydroxyl, CN, CH₃ and CF₃, and,    -   X is O, S or NCN.

The invention also preferably relates to compounds of general formula IIin which:

-   -   R1 is a linear or branched alkyl group containing from 1 to 4        carbon atoms;    -   R2 is a linear or branched alkyl group containing from 1 to 4        carbon atoms or a group (CH₂)_(n)OH, in which n is an integer        from 1 to 4 inclusive;    -   R3 is a linear or branched alkyl group containing from 1 to 4        carbon atoms, a cycloalkyl group containing from 3 to 6 carbon        atoms, an aryl group chosen from phenyl and thienyl, which may        be unsubstituted or substituted with a group chosen from        halogen, hydroxyl, methoxy, NH2 and CH₃; and    -   X is S or O.

The invention also preferably relates to the compounds of generalformula I in which:

-   -   R1 is a linear or branched alkyl group containing from 1 to 4        carbon atoms;    -   R2 is a linear or branched alkyl group containing from 1 to 4        carbon atoms or a group (CH₂)_(n)OH, in which n is an integer        from 1 to 4 inclusive;    -   R3 is a linear or branched alkyl group containing from 1 to 4        carbon atoms, a cycloalkyl group containing from 3 to 6 carbon        atoms, an aryl group chosen from phenyl and thienyl, which may        be unsubstituted or substitued with a group chosen from halogen,        hydroxyl, methoxy, NH₂, CH₃; and    -   X is S.

Among the groups defined above, the following substituents areparticularly preferred:

The linear or branched alkyl group contains from 1 to 6 carbon atoms andpreferably from 1 to 4 carbon atoms. Examples of such groups are, interalia, methyl, ethyl, n-propyl and isopropyl, tert-butyl, n-butyl,sec-butyl and isobutyl.

The linear or branched alkenyl group contains from 2 to 6 carbon atoms,preferably 2 to 4 carbon atoms. Examples comprise ethylidene,propylidene and butylidene.

The alkylcycloalkyl group comprises a linear or branched alkyl groupcontaining from 1 to 6 carbon atoms, particularly from 1 to 4 carbonatoms, and a cycloalkyl group containing from 3 to 6 carbon atoms.Examples include methylcyclopropyl, methylcyclobutyl andmethylcyclohexyl.

The cycloalkyl group comprises from 3 to 6 carbon atoms. Examples arecyclopropyl, cyclopentyl and cyclohexyl.

The aryl group is an aromatic group containing from 5 to 10 carbonatoms. Examples of such groups are phenyl, benzyl, tolyl and naphthyl.This aryl group can optionally be interrupted with a hetero atom chosenfrom nitrogen, oxygen and sulphur. The term “interrupted” means that thehetero atom can replace a carbon atom of the ring. Examples of suchgroups containing a hetero atom are, inter alia, thienyl and pyridyl.

The term alkylaryl corresponds to a group containing an alkyl grpup andan aryl group as defined above, linked to the rest of the molecule viathe aryl group.

The term arylalkyl corresponds to a group containing an alkyl group andan aryl group as defined above, linked to the rest of the molecule viathe alkyl group.

The aryl, alkylaryl and arylalkyl groups defined above can beunsubstituted or substituted on the aryl group with 1, 2 or 3 groupschosen from:

halogen, hydroxyl, NO, NO₂, alkoxy containing from 1 to 4 carbon atoms,(CH₂)_(n)NR_(B)R_(C), (CH₂)_(n)NC(O)R_(B), (CH₂)_(n)OR_(B),(CH₂)_(n)HNSO₂R_(B), CO₂R_(B), CF₃ and

in which R_(B), R_(C) and n are as defined above.

Halogen comprises chlorine, bromine, fluorine and iodine.

The compounds listed below are among the preferred compounds of thepresent invention:

-   1-Ethyl-5-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(4-Bromophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1,3-Dimethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(4-Methoxyphenyl)-1,3-dimethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(4-Bromophenyl)-1,3-dimethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-naphth-2-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(3-Chlorothien-2-yl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   Methyl    3-(1-ethyl-3-methyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)propanoate,-   1-Ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(4-Chlorophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(4-Aminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(4-fluorophenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(3-Bromophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Methyl-5-phenyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Isopropyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   (±)1-Ethyl-3-methyl-5-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-(2-Hydroxyethyl)-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   1-Ethyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(3-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(2-Aminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(2-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,    isomer 1,-   1-Ethyl-3-methyl-5-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,    isomer 2,-   3-Methyl-5-phenyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   1-Ethyl-3-methyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(3-Aminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   5-(4-Aminophenyl)-3-tert-butyl-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(4-Aminophenyl)-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(4-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(4-Aminophenyl)-3-methyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Methyl-5-phenyl-1-(2,2,2-trifluoroethyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1,5-Diethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-Cyclohexyl-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   (±)1-Ethyl-3-methyl-5-pyrid-4-yl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-tert-Butyl-1-ethyl-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(4-Diethylaminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   N-[4-(1-Ethyl-3-methyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)phenyl]acetamide,-   4-(1-Ethyl-3-methyl-8-oxo-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,-   5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   4-(1-Ethyl-3-isopropyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,-   1-Ethyl-3-isopropyl-5-(4-pyrrolidin-1-yl-phenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(2,4-Dimethoxyphenyl)-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-tert-Butyl-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Isopropyl-1-propyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   4-(3-Isopropyl-8-oxo-1-propyl-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,-   3-Isopropyl-1-propyl-5-(4-pyrrolidin-1-yl-phenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(2,4-Dimethoxyphenyl)-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3,5-Di-tert-butyl-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   4-(3-tert-Butyl-1-ethyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,-   3-tert-Butyl-1-ethyl-5-(4-pyrrolidin-1-yl-phenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-5-(2,4-dimethoxyphenyl)-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3,5-Di-tert-butyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-propyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   4-(3-tert-Butyl-8-oxo-1-propyl-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,-   3-tert-Butyl-1-propyl-5-(4-pyrrolidin-1-yl-phenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-5-(2,4-dimethoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   1-Ethyl-3-methyl-5-pyrid-3-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-pyrid-2-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-phenyl-1,6-dihydropyrazolo[4,3-e][1,4]diazepin-8-ylcyanamide,-   N-[4-(1-Ethyl-3-methyl-8-oxo-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)phenyl]-(phenylsulphonyl)benzenesulphonamide,-   (1-Ethyl-3-methyl-5-phenyl-1,6-dihydropyrazolo[4,3-e][1,4]diazepin-8-yl)methylamine,-   1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   1-Cyclopentyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Cyclopropylmethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Cyclobutylmethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Allyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-(4-trifluoromethylphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-isopropyl-5-(4-trifluoromethylphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-(4-trifluoromethylphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Isopropyl-1-propyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   3,5-Di-tert-butyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   5-tert-Butyl-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   (±)3-sec-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   (±)3-sec-Butyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   (±)3-sec-Butyl-5-phenyl-1-propyl-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   (±)3-sec-Butyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexyl-1-ethyl-5-phenyl-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexyl-5-phenyl-1-propyl-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexylmethyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexylmethyl-5-phenyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexylmethyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexylmethyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-8-oxo-5-phenyl-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-3-carboxylic    acid ethyl ester,-   5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   1-Ethyl-3-isopropyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   1-Ethyl-5-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   3-Isopropyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(4-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   (±)3-sec-Butyl-1-ethyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   (±)3-sec-Butyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-(3,4,5-trimethoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(3-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(2-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-(2,3,4-trimethoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3,5-diphenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(4-hydroxyphenyl)-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(4-Hydroxyphenyl)-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-(4-hydroxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(2,6-Dimethoxyphenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Ethoxymethyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

Among the preferred compounds defined above, the following compounds arepreferred:

-   1-Ethyl-5-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(4-Bromophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-naphth-2-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(3-Chlorothien-2-yl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   Methyl    3-(1-ethyl-3-methyl-8-oxo-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)propanoate,-   5-(4-Chlorophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(4-Aminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(4-fluorophenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(3-Bromophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Methyl-5-phenyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-(2-Hydroxyethyl)-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   1-Ethyl-5-(3-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(2-Aminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(2-methoxyphenyl)-3-methyl-6,7-dihydro-1H-yrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(3-Aminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   5-(4-Aminophenyl)-3-tert-butyl-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(4-Aminophenyl)-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(4-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(4-Aminophenyl)-3-methyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Methyl-5-phenyl-1-(2,2,2-trifluoroethyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-Cyclohexyl-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-tert-Butyl-1-ethyl-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   4-(1-Ethyl-3-isopropyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,-   5-(2,4-Dimethoxyphenyl)-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-tert-Butyl-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Isopropyl-1-propyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   4-(3-Isopropyl-8-oxo-1-propyl-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,-   5-(2,4-Dimethoxyphenyl)-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3,5-Di-tert-butyl-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   4-(3-tert-1ethyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,-   3-tert-Butyl-5-(2,4-dimethoxyphenyl)-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3,5-Di-tert-butyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-propyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   4-(3-tert-Butyl-8-oxo-1-propyl-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,-   3-tert-Butyl-5-(2,4-dimethoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   1-Ethyl-3-methyl-5-pyrid-3-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-pyrid-2-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-phenyl-1,6-dihydropyrazolo[4,3-e][1,4]diazepin-8-ylcyanamide,-   N-[4-(1-Ethyl-3-methyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)phenyl]-(phenylsulphonyl)benzenesulphonamide,-   1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   1-Cyclopropylmethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Allyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-(4-trifluoromethylphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-isopropyl-5-(4-trifluoromethylphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-(4-trifluoromethylphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Isopropyl-1-propyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   3,5-Di-tert-butyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   5-tert-Butyl-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   (±)3-sec-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   (±)3-sec-Butyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   (±)3-sec-Butyl-5-phenyl-1-propyl-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   (±)3-sec-Butyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexyl-1-ethyl-5-phenyl-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexyl-5-phenyl-1-propyl-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexylmethyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexylmethyl-5-phenyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexylmethyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexylmethyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-8-oxo-5-phenyl-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-3-carboxylic    acid ethyl ester,-   5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   1-Ethyl-3-isopropyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   1-Ethyl-5-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   3-Isopropyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(4-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   (±)3-sec-Butyl-1-ethyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   (±)3-sec-Butyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-(3,4,5-trimethoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(3-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(2-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3,5-diphenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(4-hydroxyphenyl)-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(4-Hydroxyphenyl)-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4)diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-(4-hydroxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Ethoxymethyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one.

Among the preferred compounds defined above, the following compounds arepreferred:

-   1-Ethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   1-Ethyl-5-(2-methoxyphenyl)-3-methyl-6,7-dihydro-1H-yrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   5-(4-Aminophenyl)-3-tert-butyl-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(4-Aminophenyl)-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(4-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-Cyclohexyl-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-tert-Butyl-1-ethyl-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   4-(1-Ethyl-3-isopropyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,-   5-(2,4-Dimethoxyphenyl)-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-tert-Butyl-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Isopropyl-1-propyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   4-(3-Isopropyl-8-oxo-1-propyl-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,-   5-(2,4-Dimethoxyphenyl)-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3,5-Di-tert-butyl-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo(4,3-e][1,4]diazepin-8-one,-   4-(3-tert-Butyl-1-ethyl-8-oxo-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,-   3-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   1-Ethyl-3-methyl-5-phenyl-1,6-dihydropyrazolo[4,3-e][1,4]diazepin-8-ylcyanamide,-   1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   (±)3-sec-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   (±)3-sec-Butyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   (±)3-sec-Butyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexylmethyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazol[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   1-Ethyl-3-isopropyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1-pyrazolo    [4,3-e][1,4]diazepin-8-ylidenecyanamide,-   3-Isopropyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(4-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   (±)3-sec-Butyl-1-ethyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-(3,4,5-trimethoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(3-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(2-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3,5-diphenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(4-hydroxyphenyl)-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(4-Hydroxyphenyl)-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-(4-hydroxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Ethoxymethyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one.

Among the preferred compounds defined above, the following compounds arepreferred:

-   1-Ethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   5-9(4-Aminophenyl)-3-tert-butyl-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(4-Aminophenyl)-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo    [4,3-e][1,4]diazepin-8-one,-   5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo    [4,3-e][1,4]diazepin-8-one,-   4-(1-Ethyl-3-isopropyl-8-oxo-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,-   5-tert-Butyl-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo    [4,3-e][1,4]diazepin-8-one,-   4-(3-Isopropyl-8-oxo-1-propyl-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,-   3,5-Di-tert-butyl-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   4-(3-tert-Butyl-1-ethyl-8-oxo-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,-   3-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo    [4,3-e][1,4]diazepin-8-thione,-   1-Ethyl-3-methyl-5-phenyl-1,6-dihydropyrazolo[4,3-e][1,4]diazepin-8-ylcyanamide,-   1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo    [4,3-e][1,4]diazepin-8-ylidenecyanamide,-   1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   (±)3-sec-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   (±)3-sec-Butyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   (±)3-sec-Butyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexylmethyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   1-Ethyl-5-(4-hydroxyphenyl)-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(4-Hydroxyphenyl)-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-(4-hydroxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one.

Among the preferred compounds of the present invention, the compoundsbelow are particularly preferred:

-   1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   5-(4-Aminophenyl)-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(4-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   4-(1-Ethyl-3-isopropyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,-   5-tert-Butyl-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   4-(3-Isopropyl-8-oxo-1-propyl-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,-   3-tert-Butyl-1-ethyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   (±)3-sec-Butyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   (±)3-sec-Butyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(2-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-(4-hydroxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide.

Derivatives of the Compounds of the Invention

The compounds used in the invention include the solvates, the hydrates,the pharmaceutically acceptable salts and the polymorphs (differentcrystal structures) of the compounds according to the invention, whichare designated as being pharmaceutically acceptable derivatives thereof.

The pharmaceutically acceptable salts include, for example: acetate,benzenesulphonate, benzoate, bicarbonate, bitartrate, bromide, calciumacetate, camsylate, carbonate, chloride, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, glycoloylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methyl nitrate, methyl sulphate, mucate, napsylate, nitrate,pamoate (embonate), pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, subacetate, succinate,sulphate, tannate, tartrate, theoclate, triethiodide, benzathine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine,procaine, aluminium, calcium, lithium, magnesium, potassium, sodium andzinc (see also “Pharmaceutical salts” by Berge S. M. et al. (1997) J.Pharm. Sci. 66: 1-19, the content of which is incorporated into thepresent invention by way of reference).

The use of a prodrug of a compound according to the invention is alsoenvisaged. (See in particular Bundgaard, et al., Acta Pharm. Suec.,1987; 24: 233-246).

Mixtures of compounds are also envisaged.

Pharmaceutical Formulation of the Compounds of the Invention

The compounds of the invention are administered in the form ofcompositions that are appropriate for the nature and seriousness of thecomplaint to be treated. The daily dosage in man is usually between 2 mgand 1 g of product, which can be absorbed in one or more intakes. Thecompositions are prepared by methods that are common to those skilled inthe art and generally comprise 0.5 to 60% by weight of active principle(compound of formula I) and 40 to 99.5% by weight of pharmaceuticallyacceptable vehicle. The compositions of the present invention are thusprepared in forms that are compatible with the desired route ofadministration. By way of example, the following pharmaceutical formsmay be envisaged, although the list given below is not limiting:

1) Forms for Oral Administration:

Tablets, cachets, sachets of powder for drinkable suspension, gelcapsules, gastro-resistant gel capsules, sustained-release forms,emulsions, HPMR wafer capsules or gel capsules, lyophilizates to bemelted under the tongue, drinkable solutions, suspensions and sachets ofpowder for a drinkable solution.,

The powders, tablets, cachets or encapsulated forms preferably containfrom 5% to 70% of active principle. Suitable supports are, for example,magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin,dextrin, starch, gum tragacanth, methylcellulose, sodiumcarboxymethylcellulose, low-melting wax, cocoa butter and the like.

The tablets, powders, cachets and capsules can be used as a unit dosagefor oral administration.

In the powders, the support is a finely divided solid, which is in amixture with the finely divided compound of general formula I.

In the tablets, the active compound is mixed with the support which hasthe required binding properties, in a suitable amount, and the mixtureis then tableted into the required shape and size.

The aqueous solutions for oral administration can be prepared bydissolving the active principle and adding, if necessary, dyes, flavourenhancers, flavourings, stabilizers, thickeners, etc. By way of example,the active principle can be dispersed in the form of finely dividedpowder in water with a viscous material such as synthetic gums, resins,methylcellulose, sodium carboxymethylcellulose and other suspensionagents known in the pharmaceutical field.

2) Forms for Parenteral Administration:

Intravenous Route:

Aqueous solutions, water/co-solvent solutions, solutions using one ormore solubilizing agents, colloidal suspensions, emulsions,nanoparticulate suspensions which can be used for injectingsustained-release forms, dispersed forms and liposomes.

Sterile solutions of the active principle in water and/or propyleneglycol can be mentioned as examples of liquid preparations which aresuitable for parenteral administration. The liquid preparations can alsobe formulated in the form of aqueous solutions of polyethylene glycol.

Subcutaneous/Intramuscular Route:

In addition to the forms that can be used intravenously which can alsobe used for the subcutaneous and intra-muscular routes, other types offorms such as suspensions, dispersed forms, sustained-release gels andsustained-release implants can also be used.

3) Forms for Topical Administration:

Among the most common topical forms are creams, gels (aqueous phasesgelled with polymers), patches, which are dressings to be stuck directlyon the skin and which can be used for treating dermatoses withoutpercutaneous penetration of the active substance, sprays, emulsions andsolutions.

4) Forms for Pulmonary Administration:

Distinguished in this category are forms such as solutions for aerosols,powders for inhalers and other suitable forms.

5) Forms for Nasal Administration:

This relates especially to solutions or suspension for drops.

6) Forms for Rectal Administration:

Suppositories and gels will be selected, inter alia.

For the preparation of suppositories, a low-melting wax, such as amixture of fatty acid glycerides and cocoa butter, is melted in a firststage, and the active principle is then dispersed therein, for examplewith mechanical stirring. The molten homogeneous mixture is then pouredinto moulds of appropriate shape and then left to cool and solidify.

It may also be envisaged to use forms allowing the administration ofophthalmic solutions or allowing the administration of the activeprinciple via the vaginal route.

Another important category of pharmaceutical form which can be used inthe context of the present invention relates to forms for improving thesolubility of the active principle. By way of example, it may beenvisaged to use aqueous solutions of cyclodextrin, and moreparticularly forms comprising hydroxypropyl beta cyclodextrin. Adetailed review of this type of pharmaceutical form is given in thearticle published under the reference Journal of PharmaceuticalSciences, 1142-1169, 85 (11), 1996, and incorporated into the presentpatent application by way of reference.

The various pharmaceutical forms recommended above are described indetail in the book <<Pharmacie galénique [Pharmaceutical pharmacy]>>byA. Lehir (published by Masson, 1992 (6th edition)), which isincorporated into the present patent application by way of reference.

Synthesis of the Compounds of the Present Invention

A subject of the invention is also a process for preparing the compoundsaccording to the invention, as illustrated in the reaction schemesbelow. The starting materials are commercially available or can besynthesized by standard methods.

Reaction Scheme 1

In the description which follows, each of the steps of the reactionscheme is described in general. This process and its various steps areexemplified in Example 1. If a step can be carried out according tovarious methods (depending on the compounds under consideration), theywill be described (M1, M2, . . . ) and identified relative to aliterature reference. The starting materials are chosen in anappropriate manner (it being possible for the reactive functions, ifany, to be protected in a conventional manner).

Step 1:

An R1-methyl ketone in which R1is one of the substituents of thecompound of general formula I is reacted with a diethyl oxalate in thepresence of sodium to give the compound of general formula A1.

Step 2:

A cyclization of the compound A1 is then carried out, for example withhydrazine sulphate in the presence of potassium hydroxide to give amixture of the pyrazole (A2) and the pyrazole (A6) each comprising thesubstituent R1. These two intermediates may be separated and reactedsubsequently.

Step 3a:

Step 3a is an alternative step to step 9 described below. It allows theintroduction of a sulphur atom into the position of the substituent Xfrom the very first steps of the synthesis, by reacting A2 or A6 with asuitable reagent, for example, Lawesson's reagent, to give a compound offormula A2a or A6a in which X is equal to O or S and R1 is defined asabove.

Step 3:

Step 3 essentially comprises the nitration of the pyrazole nucleus. Thisnitration is carried out on the compounds A2, A2a, A6, A6a, A8 or A9 andcan be carried out according to 3 methods desribed in the literature:

-   -   using NaNO₃/H₂SO₄ (method M1), see Example 1; Aust. J. Chem.,        47, 1009-1021, 1994;    -   using HNO₃/H₂SO₄, (method M2);    -   or using Cu(NO₃)₂ (method M3), J. Org. Chem., 46, 3056-3060,        1981 to give a compound of formula A, A3, A4, A5 or A7 in which        X is equal to O or S.        Step 4:

In this step, compound A3 is esterified. This can be carried out byreacting compound A3 with ethanol in acidic medium. Compound A4 in whichX is equal to O or S and R1 is as defined above is thus obtained.

Step 5:

The pyrazoles A2, A4, A6 and A7 are alkylated according to variousmethods:

-   -   by reacting dimethyl sulphate (to give derivatives with        R2=ethyl) (methode M4), J. Med. Chem. 16, 12, 1346-1354, 1973;    -   by reacting with a compound of the type R2-hal, in which R2 is        as defined for the compound of general formula I and hal is a        halogen (method M5).

A compound of formula A5, A8 or A9 in which X is equal to O or S isobtained.

Step 6:

During this step, the ester function (X═O) or thioester function (X═S)is hydrolysed, for example by reacting compound AS with sodiumhydroxide. This gives compound A in which X is equal to O or S and R1and R2 are as defined above.

Step 7:

During this step, compound A is reacted with compound B of generalformula

in which R3 is one of the substituents of the compound of generalformula I. Preferably, a hydrochloride of compound B is used. When it isnot commercially available, the product (B) is synthesized in one step(step 7a), starting with compound (B1), which is commercially availableor described in the literature. The nucleophilic substitution of thebromine with the primary amine function is obtained according to variousmethods:

-   -   Delepine method (method M6), J. Heterocyclic Chem., 24, 297-301,        1987.    -   Method via the synthesis of a bisformamide (method M7),        Tetrahedron. Lett., 30, 39, 5285-58-286, 1889; Synthesis,        122-124, 1990.

Compound C in which X is equal to O or S is obtained according tovarious coupling methods (step 7):

-   -   Method of coupling N-hydroxysuccinimide and        dicyclohexylcarbodiimide (method M8, see example 1)    -   Method of coupling on a solid support (method M9): compound A (1        eq.) is reacted with N-cyclohexylcarbodiimide and        N′-methylpolystyrene HL (2 eq.) in dichloromethane. After        stirring for half an hour, compound B (1 eq.) and triethylamine        (1 eq.) are added. After 24 hours at room temperature, methyl        isocyanate polystyrene HL is added. After 2 hours, the reaction        medium is filtered and the filtrate is concentrated to give        compound C in which X is equal to O or S.    -   Method of coupling with EDCI        1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride and        HOBt (1-hydroxybenzotriazole) (method M10): compound B is        reacted, with stirring, with compound A in equimolar amount in        dichloromethane in the presence of one equivalent of        triethylamine, one equivalent of 1-hydroxybenzotriazole and one        equivalent of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide        hydrochloride. After 24 hours at room temperature, the reaction        medium is washed with water; the organic phase is dried and        evaporated to dryness to give the compound of formula C in which        X is equal to O or S and R1, R2 and R3 are as defined above.        Step 8:

During this step, compound C is cyclized according to various methods togive compound D in which X is equal to O or S and R1, R2 and R3 are asdefined above:

-   -   using Fe/HCl (method M11) (see example 1);    -   using SnCl₂ (method M12): an amide of type C is dissolved in        ethanol with 5 equivalents of tin chloride dihydrate. The        reaction medium is refluxed for 4 hours. After cooling to room        temperature, demineralized water is added and, when cold, the        solution is brought to basic pH with 30% sodium hydroxide. After        extraction with CH₂Cl₂ and drying, the medium is evaporated to        dryness to give the compound of type D, which is purified, if        necessary, on silica or by crystallization.        Step 9:

Step 9 is used when it is desired to obtain a compound of formula I inwhich X is S if, in compound D, X is O. The compounds of this type areobtained by reacting compound D, in which X is O, with a suitablereagent, allowing its thionation to be carried out. By way of example,Lawesson's reagent may be used. A compound of formula E in which X is Sis thus obtained.

Steps 10 and 11:

Steps 10 and 11 are used when it is desired to obtain a compound offormula I in which X is N—CN. The compounds of this type are obtainedaccording to various methods:

-   -   method M13: by reacting compound E with sodium hydride and then        with iodomethane to give compound (G). This compound is then        placed in contact with cyanamide and triethylamine to give a        compound of type (F); Heterocycles, 36, 777-783, 1993.    -   method M14: Ph₃PSnN═C═NSnPPh₃ in ethanol; J. Med. Chem., 35, 12,        2327-2340, 1992.    -   method M15: phosphoryl chloride, cyanamide and triethylamine;        Chem. Pharm. Bull., 42, 12, 2475-2482, 1994.    -   method M16: cyanamide, triethylamide [sic], mercury acetate and        acetonitrile; Can. J. Chem., 63, 3089-3101, 1985.        Steps 11a and 11b:

Step 11a makes it possible to reduce the imine function of compound D byreacting it with a reducing agent, for example NaBH₄ in a polar mixture,for example methanol/water in the presence of palladium-on-charcoal togive the racemate D1 in which X is O or S and R1, R2 and R3 are asdefined above, and the following step (11b) corresponds to theseparation of the enantiomers (isomer 1 and isomer 2), for example bymeans of HPLC on a Diacel OD-H chiral column (250 mm×4.6 mm, 5 μm, flowrate 1 ml/min, 80/20 heptane/isopropanol).

These steps, 11a and 11b, also apply in the case of a compound offormula D in which X is N—CN or N—R_(B).

Steps 10 and 12:

Steps 10 and 12 are used to obtain compounds of the type H. Step 10allows the formation of the derivative G and step 12 leads to theintroduction of the group N—RB according to a method inspired by theliterature: J. Med. Chem., 42, 2909-2919, 1999.

Reaction scheme 2:

This reaction scheme results in the synthesis of derivatives D in whichX is O with R1=aryl containing from 5 to 10 carbon atoms, optionallyinterrupted with a hetero atom chosen from nitrogen, oxygen and sulphurand R2 and R3 are as defined above. This process is illustrated byExample 4.

Step 14:

The synthesis of the pyrazole is carried out under the conditionsdescribed in Farmaco Ed. Sci., 39, 7, 1984, 618-636.

Step 15:

During this step, the ester function of compound K is hydrolysed, forexample by reacting compound K with sodium hydroxide. This givescompound L.

Step 16:

This step leads to the formation of the derivative M after coupling withcompound B and cyclization.

Step 17:

This step allows the formation of the compounds D with X═O and R1=arylcontaining from 5 to 10 carbon atoms, optionally interrupted with ahetero atom chosen from nitrogen, oxygen and sulphur and R2 and R3 areas defined above.

Compound M is alkylated by reacting it with a compound of the typeR2-hal, in which R2 is as defined for the compound of general formula Iand hal is a halogen. Compound D is thus obtained.

Reaction Scheme 3

This scheme describes the synthesis of compounds D withR1=(CH₂)_(n)OR_(B) or (CH₂)_(n)COOR_(B). These molecules can lead, viastandard reactions of organic chemistry, to the formation of compounds Dwith R1=(CH₂)_(n)C(O)R_(B), (CH₂)_(n)OC(O)R_(A), (CH₂)_(n)SR_(B),(CH₂)_(n)NR_(B)R_(C), (CH₂)_(n)C(O)NR_(B)R_(C), (CH₂)_(n)NR_(C)C(O)R_(B)or (CH₂)_(n)Z with n, R_(A), R_(B), R_(C) and Z as described above.

Steps 3, 5, 7 and 8 are described above in general.

Steps 5, 18, 3, 7 and 8 are illustrated by Example 5 and steps 19, 20and 21 by Example 97.

Step 22:

This cyclization step is carried out in acidic medium, for example 5%HCl, in an aprotic solvent such as tetrahydrofuran, to give the hydroxyderivative D with R1=CH₂OH.

Step 23:

This step leads to the synthesis of various derivatives D (R1=OR_(B))using, for example, a compound of the type RB-hal, in which R_(B) is asdefined above and hal is a halogen.

Step 21:

This step is limited to the use of hydroxylated solvents such as MeOHand EtOH, during the cyclisation step of compound T, also allows thesynthesis of compounds D with R1=OR_(B).

Reaction Scheme 4

This is an alternative method for sythesizing the compounds of generalformula I in which X is O or S and R1, R2 and R3 are as defined above.This alternative method is illustrated in the scheme below.

Reaction Scheme 5

This is another method for synthesizing compounds of general formula Iin which X is O or S. This method is illustrated in summary in thescheme given below. A more detailed description of this synthesis ispresented in U.S. Pat. No. 5,272,147, the content of which isincorporated into the present patent application by reference.

EXAMPLES Example 11-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=isopropyl; R2=ethyl; R3=phenyl)

Step 1:

0.37 g (0.0138 mol) of sodium is dissolved portionwise in 40 ml ofanhydrous ethanol under nitrogen at room temperature. 1.86 ml (13.6mmol) of diethyl oxalate in 10 ml of anhydrous ethanol are added. 1.47ml (13.6 mmol) of isopropyl methyl ketone are added. The reactionmixture is left stirring overnight at room temperature (RT) and is thenevaporated to dryness. The product obtained is isolated in the form ofan orange powder (compound A1): m=3.1 g (100%).

MS (ES+), m/z=185

Rf (CH₂Cl₂/acetone 90/10)=0.91

Step 2:

0.98 g (14.8 mmol) of potassium hydroxide is dissolved in 7.5 ml ofwater and the reaction medium is cooled to 0° C. 3.1 g (14.8 mmol) ofcompound A1 (see scheme 1) are added portionwise and the mixture isstirred for 30 min at 0° C. 1.94 g (14.8 mmol) of hydrazine sulphate areadded and the mixture is then stirred for 45 min at 0° C. Afterfiltration, the precipitate is rinsed with a small amount of water andthen dried to give 0.93 g (13%) of a white powder (compound A2).

¹H NMR (DMSO, 400 MHz)

1.2 ppm (6H, d); 2.95 ppm (1H, m); 6.45 ppm (1H, s); 12.3 ppm (1H, m)

Step 3:

Method M1 is used. 100 ml of concentrated H₂SO₄ are introduced into around-bottomed flask. The flask is cooled to 0° C. and 10.09 g (0.065mol) of compound A2 (see scheme 1) (0.065 mol) are added, followed byaddition of 16.5 g (0.195 mol) of NaNO₃. The mixture is warmed to RT andstirred for 24 h. The reaction medium is poured gently into 200 ml ofice-cold water, cooling the flask if necessary, and stirred for 30 min.The precipitate is filtered off and rinsed with water. After drying,4.25 g (33%) of a white powder are obtained (compound A3).

MS (ES−) m/z=198

¹H NMR (DMSO, 400 MHz)

1.3 ppm (6H, d); 3.5 ppm (1H, m); 13.9 ppm (2H, m)

Step 4:

A mixture of 4.25 g of compound A3 (0.021 mol), 24 ml of ethanol and 2.3ml of concentrated H₂SO₄ in a round-bottomed flask is refluxed for 4.5h. The reaction medium is evaporated and then taken up in CH₂Cl₂ andwashed with water; after drying over MgSO₄, the organic phase isfiltered and then concentrated to give 4 g (83%) of powder (compoundA4).

MS (ES+), m/z=228

Rf (CH₂Cl₂/MeOH95/5)=0.52

Step 5:

Method M5 is used. 2.77 g (0.02 mol) of K₂CO₃ are added under a streamof nitrogen to a solution of 4 g (0.02 mol) of compound A4 in 40 ml ofanhydrous DMF, followed by addition of 1.76 ml (0.022 mol) ofiodoethane. The reaction medium is heated at 60° C. for 16.5 h. Afterfiltering off the precipitate, the filtrate is taken up in diethylether(100 ml) and this organic phase is washed with water, dried over MgSO₄,filtered and then concentrated to give 4 g of an oily compound.

This crude product is purified by flash chromatography on a column ofsilica using the following elution gradient: from 50/50 CH₂Cl₂/heptaneto 80/20 CH₂Cl₂/heptane to give 2.92 g (57%) of a yellow oil (compoundA5).

MS (ES+), m/z=256

¹H NMR (CDCl₃, 400 MHz)

1.3 ppm (6H, d); 1.35 ppm (3H, t); 1.45 ppm (3H, t); 3.45 ppm (1H, m);4.2 ppm (2H, g); 4.45 ppm (2H, q)

Step 6:

2.92 g (0.011 mol) of compound A5 (see scheme 1) are introduced into 15ml of methanol in a round-bottomed flask, followed by addition of asolution of 0.68 g (0.0165 mol) of sodium hydroxide in 15 ml of water.The mixture is stirred at RT for 3 h. After evaporating off themethanol, the residue is taken up in CH₂Cl₂, an identical volume ofwater is added and the resulting mixture is then acidified (withstirring) with concentrated (36%) HCl. After separation of the phases bysettling, the organic phase is dried over Na₂SO₄ and concentrated togive 2.3 g of a white powder (92%) (compound A).

MS (ES−), m/z=226

¹H NMR (DMSO, 400 MHz),

1.2 ppm (6H, d); 1.35 ppm (3H, t); 3.35 ppm (1H, m); 4.15 ppm (2H,q)

Step 7:

Method M8 is used. 1 g (4 mmol) of compound A (see scheme 1) isdissolved in a mixture of 25.7 ml of THF and 1.4 ml of DMF, followed byaddition, under nitrogen, of 0.51 g (4 mmol) of N-hydroxysuccinimide.The reaction medium is cooled to 0° C. so as to add portionwise 0.91 g(4 mmol) of dicyclohexylcarbodiimide. The mixture is stirred overnightat RT. The precipitate formed is filtered off and the filtrate isevaporated to dryness. The residue is taken up in 20 ml of CH₂Cl₂, 0.75g (4 mmol) of 2-aminoacetophenone hydrochloride is added under nitrogen,the reaction medium is cooled to 0° C., 0.61 ml (4 mmol) oftriethylamine is then added and the mixture is stirred at RT for 3 h.The reaction medium is poured into water with stirring. After extractionwith dichloromethane, washing with water and drying over Na₂SO₄, theorganic phase is evaporated to dryness to give 1.3 g (86%) of a whitepowder (compound C).

MS (ES+), m/z=345

¹H NMR (CDCl₃, 400 MHZ),

1.35 ppm (6H, d); 1.5 ppm (3H, q); 3.55 ppm (1H, m); 4.3 ppm (2H, q); 5ppm (2H, d); 7.5 ppm (2H, t); 7.65 ppm (1H, d); 7.7 ppm (1H, m); 8 ppm(2H, d).

Step 8:

Method M11 is used. 1.3 g (3.7 mmol) of compound C (see scheme 1) areintroduced into a mixture of 30 ml of ethanol and 7 ml of water in around-bottomed flask, followed by addition of 2.2 g (3.9 mmol) of ironand 0.5 ml of conc. (36%) HCl. The reaction medium is refluxed for 1 h15 min. The iron is removed by filtration. The filtrated is concentratedto dryness and the residue is taken up in CH₂Cl₂ and washed with twice70 ml of water and then with saturated NaCl solution; the organic phaseis dried over Na₂SO₄, filtered and concentrated to give an amorphous redpowder (m=0.9 g).

This crude product is purified by flash chromatography using thefollowing elution gradient: 98/2 CH₂Cl₂/acetone to 90/10 CH₂Cl₂/acetone.

The red powder obtained after evaporation is taken up in the minimumamount of diethyl ether and then filtered. After drying, 0.35 g (32%) ofa beige powder (compound D) is isolated.

MS (ES+), m/z=297

m.p.=157.2° C.

¹H NMR (CDCl₃, 400 MHZ),

1.4 ppm (6H, d); 1.5 ppm (3H, t); 3.35 ppm (1H, m); 4.1 ppm (2H, d);4.55 ppm (2H, q); 6.25 ppm (1H, m); 7.45 ppm (3H, m); 8.0 ppm (2H, m).

Example 21-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione

(R1=isopropyl; R2=ethyl; R3=phenyl)

Step 9:

0.2 g (0.67 mmol) of compound D (see scheme 1) is dissolved in 7 ml oftoluene over sieves, and 0.54 g (1.34 mmol) of Lawesson's reagent isadded, under nitrogen. The mixture is refluxed for 16.5 h. The reactionmedium is cooled to RT; 2 ml of 5% HCl are then added, followed by 25 mlof methanol and 25 ml of cyclohexane, the mixture is stirred, theprecipitate is then filtered off and the two phases are allowed toseparate by settling. The methanol phase is evaporated. The residue istaken up in ethyl acetate and washed with water; the organic phase isdried over Na₂SO₄, filtered and evaporated.

The crude product is purified by flash chromatography (80/20cyclohexane/ethyl acetate). After evaporation, 0.15 g (75%) of a yellowpowder (compound E) is obtained.

MS (ES+), m/z=313

m.p.=164° C.

¹H NMR (CDCl₃, 400 MHz),

1.4 ppm (6H, d); 1.5 ppm (3H, t); 3.3 ppm (1H, m); 4.2 ppm (2H, m); 4.8ppm (2H, q); 7.45 ppm (3H, m); 8 ppm (2H, d); 8.3 ppm (1H, m)

Example 31-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide

(R1=isopropyl; R2=ethyl; R3=phenyl)

Step 10:

According to M13, 1.83 g (5.86 mmol) of1-ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thioneare reacted with 0.18 g of 80% sodium hydride in refluxing THF for 1 h,and 0.44 ml of methyl iodide is then added at room temperature. Themixture is refluxed for 2 h to give 1.53 g (80%) of the expectedmethylsulphanyl of type G (see Scheme 1).

m.p.=98° C.

MS (ES+), m/z=327

¹H NMR (DMSO, 400 MHz), 8.1 ppm (2H, d); 7.4 ppm (3H, m); 4.4 ppm (4H,m); 3.2 ppm (1H, m); 2.4 ppm (3H, s); 1.4 ppm (3H, t); 1.3 ppm (6H, m)

Step 11:

0.5 g (1.53 mmol) of the methylsulphanyl G is reacted with 0.12 g (2eq.) of cyanamide to give 0.396 g (81%) of the expected product of typeF (see Scheme 1).

m.p.=222° C.

MS (ES+), m/z=321

¹H NMR (DMSO, 400 MHz), 9.4 ppm (1H, 1s); 8 ppm (2H, m); 7.4 ppm (3H,m); 4.3 ppm (2H, g); 4.1 ppm (2H, 1s); 3.1 ppm (1H, m); 1.3 ppm (3H, t);1.2 ppm (6H, d)

Example 41-Ethyl-3,5-diphenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,

(R1=phenyl; R2=ethyl; R3=phenyl)

Step 15:

35.75 g (0.15 mol) of compound K (see scheme 2) in 35 ml of methanol areintroduced into a round-bottomed flask, followed by addition of asolution of 9.24 g (0.231 mol) of sodium hydroxide in 140 ml of water.The mixture is stirred at room temperature overnight. After evaporation,the residue is taken up in ethanol and then filtered and dried to give26.7 g (87%) of a beige powder (compound L, see scheme 1).

MS (ES+), m/z=203.9

¹H NMR (DMSO, 400 MHz) 4.7 ppm (2H, m); 7.2 ppm (1H, m); 7.3 ppm (2H,t); 7.75 ppm (2H, d); 12.2 ppm (1H, m)

Step 16:

1.5 g (8.7 mmol) of 2-aminoacetophenone hydrochloride are dissolved in amixture of 50 ml of THF and 10 ml of DMF, followed by addition of 1.22ml (8.7 mmol) of triethylamine, 1.34 g (8.7 mmol) of1-hydroxybenzotriazole hydrate and then 1.77 g (8.7 mmol) of compound L(see scheme 2) and finally 1.37 g (8.7 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The mixture is heated at60° C. for 24 h. The precipitate formed is filtered off and the filtrateis taken up in water. After extraction with ethyl acetate, the extractsare washed with water and dried over Na₂SO₄. The organic phase isevaporated to dryness to give 1.8 g of an orange powder. This crudeproduct is purified by flash using the following elution gradient: fromCH₂Cl₂ to 95/5 CH₂Cl₂/methanol to give 0.45 g (16%) of a beige powder(compound M, see scheme2).

MS (ES+), m/z=303

¹H NMR (DMSO, 400 MHz) 4.15 ppm (2H, m); 7.3-7.55 ppm (6H, m); 8-8.1 ppm(4H, m); 8.3 ppm (1H, m); 14 ppm (1H, m)

Step 17:

According to M5, 1.23 g (8.9 mmol) of K₂CO₃ are added, under a stream ofnitrogen, to a solution of 2.7 g (8.9 mmol) of compound M (see scheme 2)in 30 ml of anhydrous DMF, followed by addition of 0.71 ml (8.9 mmol) ofiodoethane. The reaction medium is heated at 60° C. overnight. Thereaction medium is extracted with diethyl ether, and the extracts aredried over Na₂SO₄, filtered and then concentrated to give 3.6 g of anoily compound. This crude product is purified by flash using thefollowing elution gradient: from CH₂Cl₂ to 98/2 CH₂Cl₂/acetone. The oilyproduct thus obtained is crystallized from diethyl ether to give 0.2 g(7%) of a yellow powder (compound (see scheme 2))

MS (ES+), m/z=331

¹H NMR (DMSO, 400 MHZ) 1.4 ppm (3H, t); 4.1 ppm (2H, m); 4.5 ppm (2H,q); 7.3 ppm (1H, m); 7.4 ppm (2H, m); 7.5 ppm (3H, m); 8 ppm (4H, m);8.5 ppm (1H, m)

Example 5 Ethyl1-ethyl-8-oxo-5-phenyl-1,6,7,8-tetrahydropyrazolo-[4,3-e][1,4]diazepin-3-carboxylate

(R1=ethyl carboxylate; R2=ethyl; R3=phenyl)

Step 5:

20 g (94 mmol) of diethyl 3,5-pyrazoledicarboxylate (commercial) arereacted with 8.3 ml (103 mmol) of iodoethane to give 21.4 g (95%) of apyrazole O (see Scheme 3)

Rf (95/5 CH₂Cl₂/MeOH)=0.70

MS (ES+), m/z=240.8

¹H NMR (CDCl₃, 400 MHz), 7.25 ppm (1H, s); 4.6 ppm (2H, q); 4.25-4.4 ppm(4H, m); 1.4 ppm (3H, t); 1.3 ppm (6H, m)

Step 18:

21 g (87 mmol) of pyrazole O (see scheme 3) are reacted, under coldconditions, in 100 ml of water and 160 ml of THF with a solution of 3.84g (96 mmol) of sodium hydroxide pellets in 100 ml of water. Afterwarming to room temperature, the reaction mixture is stirred for 2hours. The mixture is then extracted with diethyl ether. The aqueousphase is acidified with 36% HCl down to pH=2 and then extracted withdichloromethane. The organic phase is dried over Na₂SO₄ and thenfiltered and concentrated to give 13.5 g (73%) of compound P(see scheme3).

Rf (80/20 CH₂Cl₂/MeOH)=0.55

MS (ES+), m/z=212.8

¹H NMR (CDCl₃, 400 MHz), 9.1-9.5 ppm (1H, m); 7.4 ppm (1H, s); 4.65 ppm(2H, q); 4.35 ppm (2H, q); 1.4 ppm (3H, t); 1.3 ppm (3H, t)

Step 3:

According to M3, 6 g (28 mmol) of compound P (see scheme3) are reactedwith 19.75 g (84 mmol) of copper nitrate hemipentahydrate in a mixtureof trifluoroacetic anhydride and chloroform, to give 6.9 g (95%) ofcompound Q (see scheme 3).

Rf (80/20 CH₂Cl₂/MeOH+0.3% HCOOH)=0.46

MS (ES⁻), m/z=255.8

¹H NMR (DMSO, 400 MHz),

4.55 ppm (2H, q); 4.3 ppm (2H, q); 1.4 ppm (3H, t); 1.3 ppm (3H, t)

Step 7:

According to M8, 3 g (11.7 mmol) of compound Q (see scheme 3) arereacted with 2 g (11.7 mmol) of 2-aminoacetophenone hydrochloride togive 4.38 g of compound R (see Scheme 3).

MS (ES+), m/z=372.8

¹H NMR (CDCl₃, 400 MHz), 7.9 ppm (3H, m); 7.55 ppm (1H, m); 7.45 ppm(2H, m); 4.9 ppm (2H, d); 4.3-4.5 ppm (4H, m); 1.45 ppm (3H, t); 1.35ppm (3H, t)

Step 8:

According to M11, 1 g (2.7 mmol) of compound R (see scheme 3) isrefluxed with 0.3 g (5.4 mmol) of iron and 0.27 ml of 36% HCl in amixture of ethanol and water to give 0.1 g (12%) of the expectedcompound D (see Scheme 3).

Rf (50/50 cyclohexane/EtOAc)=0.19

SM (ES⁺), m/z=327

¹H NMR (CDCl₃, 400 MHz), 8.55 ppm (1H, m); 8.05 ppm (2H, m); 7.55 ppm(3H, m); 4.55 ppm (2H, q); 4.3 ppm (2H, q); 4.1 ppm (2H, d); 1.4 ppm(3H, t); 1.3 ppm (3H, t)

Example 61-Ethyl-5-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=4-methoxyphenyl)

Step 7:

According to M8, 0.5 g (2.5 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid (see J. Med.Chem., 16, 1973, 1346-1354 or U.S. Pat. No. 3,700,657) is reacted with0.5 g of 2-amino-4′-methoxyacetophenone hydrochloride to give 0.78 g(90%) of an amide of type C (see Scheme 1).

m.p.: 151° C.

Analysis calculated for C₁₆H₁₈N₄O₅

C, 55.49; H, 5.24; N, 16.11; O, 23.10

found: C, 55.45; H, 5.44; N, 16.09; O, 22.9

Step 8:

Acording to M11, 0.6 g (1.73 mmol) of the amide C (see scheme 1) isrefluxed with 1.04 g of iron and 0.173 ml of 36% HCl in an ethanol/watermixture to give 0.35 g (70%) of the expected product D (see scheme 1).

m.p.: 178° C.

MS (ES⁺), m/z=299

¹H NMR (CDCl₃, 400 MHz), 7.8 ppm (2H, d); 6.9 ppm (2H, d); 6.0 ppm (1H,t); 4.5 ppm (2H, q); 4.2 ppm (2H, d); 3.8 ppm (3H, s); 2.4 ppm (3H, s);1.45 ppm (3H, t)

Example 75-(4-Bromophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=4-bromophenyl)

Step 7:

According to M8, 0.5 g (2.5 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid is reacted with0.51 g of 2-amino-4′-bromoacetophenone hydrochloride to give 0.57 g(60%) of an amide of type C (see Scheme 1).

m.p.: 184° C.;

¹H NMR (CDCl₃, 400 MHz), 8.0 ppm (1H, s); 7.8 ppm (2H, d); 7.6 ppm (2H,d); 4.9 ppm (2H, s); 4.3 ppm (2H, q); 2.5 ppm (3H, s); 1.5 ppm (3H, t)

Analysis calculated. for C₁₅H₁₅BrN₄O₄

C, 45.59; H, 3.83; Br, 20.22; N, 14.18; O, 16.19

found: C, 45.42; H, 3.74; Br, 19.99; N, 14.11; O, 16.22

Step 8:

According to M11, 0.475 g (1.2 mmol) of the amide C (see scheme 1) isrefluxed with 0.721 g of iron and 0.12 ml of 36% HCl in an ethanol/watermixture to give 0.25 g (60%) of the expected product D (see Scheme 1).

m.p.: 223° C.

MS (ES⁺), m/z=348

¹H NMR (CDCl₃, 400 MHz), 7.8 ppm (2H, d); 7.5 ppm (2H, d); 6.2 ppm (1H,s); 4.5 ppm (2H, q); 4.0 ppm (2H, s); 2.3 ppm (3H, s); 1.4 ppm(3H, t)

Example 81-Ethyl-3-methyl-5-naphth-2-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=naphthyl)

Step 7:

According to M8, 0.45 g (2.25 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid is reacted with0.5 g of 2-amino-1-naphth-2-yl-ethanone hydrochloride to give 0.588 g(75%) of an amide of type C (see Scheme 1).

Rf (5/5 cyclohexane/EtOAc)=0.25

¹H NMR (CDCl₃, 400 MHz),

8.6 ppm (1H, t); 8.0 ppm (7H, m); 5.15 ppm (2H, d); 4.4 ppm (2H, q); 2.6ppm (3H, s); 1.5 ppm (3H, t)

Step 8:

0.58 g (1.58 mmol) of amide C (see scheme 1) is refluxed with 0.948 g ofiron and 0.158 ml of 36% HCl in an ethanol/water mixture to give 0.32 g(79%) of the expected product D (see Scheme 1).

m.p.: 193° C.

MS (ES⁺), m/z=319

¹H NMR (CDCl₃, 400 MHz), 8.2 ppm (2H, m); 7.8 ppm (3H, m); 7.5 ppm (2H,m), 6.4 ppm (1H, t); 4.5 ppm (2H, q); 4.2 ppm (2H, d); 2.4 ppm (3H, s);1.45 ppm (3H, t)

Example 95-(3-Chlorothien-2-yl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=chlorothienyl)

Step 7:

According to M8, 0.235 g (1.18 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid is reacted with0.5 g of 2-amino-1-(3-chlorothien-2-yl)ethanone hydrochloride to give0.32 g (76%) of an amide of type C (see Scheme 1) in which R1, R2 and R3are as defined in this example.

Rf (5/5 cyclohexane/EtOAc)=0.53

¹H NMR (CDCl₃, 400 MHz), 7.9 ppm (1H, m); 7.7 ppm (1H, d); 7.1 ppm (1H,d); 5.0 ppm (2H, d); 4.45 ppm (2H, q); 2.6 ppm (3H, s); 1.5 ppm (3H, t)

Step 8:

According to M11, 0.31 g (0.87 mmol) of the amide C (see scheme 1) isrefluxed with 0.52 g of iron and 0.087 ml of 36% HCl in an ethanol/watermixture to give 0.135 g (50%) of the expected product D (see Scheme 1).

m.p.: 213° C.

MS (ES⁺), m/z=309

¹H NMR (CDCl₃, 400 MHz), 7.4 ppm (1H, d); 6.9 ppm (1H, d); 6.1 ppm (1H,t); 4.55 ppm (2H, q); 4.3 ppm (2H, d); 2.4 ppm (3H, s); 1.45 ppm (3H, t)

Example 10 Methyl3-(1-ethyl-3-methyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)propanoate

(R1=methyl; R2=ethyl; R3=methyl propanoate)

Step 7:

According to M8, 0.44 g (2.21 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid is reacted with0.41 g (1 eq.) of methyl 5-amino-4-oxopentanoate hydrochloride to give0.63 g (87%) of an amide of type C (see scheme 1).

Rf (95/5 CH₂Cl₂/methanol)=0.48

¹H NMR (CDCl₃, 400 MHz), 7.7 ppm (1H, m); 4.4 ppm (2H, d); 4.3 ppm (2H,q); 3.7 ppm (3H, s); 2.85 ppm (2H, dd); 2.7 ppm (2H, dd); 2.5 ppm (3H,s); 1.5 ppm (3H, t)

Step 8:

According to M11, 0.6 g (1.83 mmol) of the amide C (see scheme 1) isrefluxed with 1.1 g of iron and 0.18 ml of 36% HCl in an ethanol/watermixture to give 0.42 g (83%) of the expected product D (see scheme 1).

m.p.: 68° C.

¹H NMR (CDCl₃, 400 MHz), 6.7 ppm (1H, t); 4.5 ppm (2H, q); 3.8 ppm (3H,s); 3.55 ppm (2H, d), 2.85 ppm (2H, t), 2.7 ppm (2H, t), 2.2 ppm (3H,s); 1.45 ppm (3H, t)

Example 115-(4-Chlorophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

R1=methyl; R2=ethyl; R3=4-chlorophenyl

Step 7:

According to M8, 0.5 g (2.5 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid is reacted with0.517 g (1 eq.) of 2-amino-4′-chloroacetophenone hydrochloride to give0.5 g (57%) of an amide of type C (see scheme 1) in which R1, R2 and R3are as defined in this example. Rf (5/5 cyclohexane/EtoAc)=0.55

¹H NMR (CDCl₃, 400 MHz), 8.0 ppm (3H, d); 7.5 ppm (2H, d); 4.95 ppm (2H,d); 4.35 ppm (2H, q); 2.5 ppm (3H, s); 1.5 ppm (3H, t)

Step 8:

According to M11, 0.45 g (1.28 mmol) of the amide C (see scheme 1) isrefluxed with 0.77 g of iron and 0.128 ml of 36% HCl in an ethanol/watermixture to give 0.27 g (70%) of the expected product D (see Scheme 1).

m.p.: 215° C.

MS (ES⁺), m/z=303

¹H NMR (CDCl₃, 400 MHz), 7.9 ppm (2H, d); 7.5 ppm (2H, d); 6 ppm (1H,t); 4.5 ppm (2H, q); 4.1 ppm (2H, d); 2.4 ppm (3H, s); 1.45 ppm (3H, t)

Example 125-(4-Aminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=4-aminophenyl)

Step 7:

According to M8, 0.5 g (2.5 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid is reacted with0.540 g (1 eq.) of 2-amino-4′-nitroacetophenone hydrochloride to give0.45 g (50%) of an amide of type C (see scheme 1).

Rf (EtOAc)=0.9

¹H NMR (CDCl₃, 400 MHz), 8.4 ppm (2H, d); 8.2 ppm (2H, d); 8.0 ppm (1H,m); 5.0 ppm (2H, d); 4.4 ppm (2H, q); 2.5 ppm (3H, s); 1.5 ppm (3H, t)

Step 8:

According to M11, 0.38 g (1.05 mmol) of the amide C (see scheme 1) isrefluxed with 0.63 g of iron and 0.105 ml of 36% HCl in an ethanol/watermixture to give 0.12 g (40%) of the expected product D (see scheme 1).

m.p.: 212° C.

MS (ES⁺), m/z=284

¹H NMR (DMSO, 400 MHz), 8.2 ppm (1H, t); 7.8 ppm (2H, d), 6.6 ppm (2H,d); 5.8 ppm (2H, s); 4.5 ppm (2H, q); 3.9 ppm (2H, d); 2.3 ppm (3H, s);1.45 ppm (3H, t)

Example 131-Ethyl-5-(4-fluorophenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=4-fluorophenyl)

Step 7:

According to M8, 0.1 g (0.53 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid is reacted with0.1 g of 2-amino-4′-fluoroacetophenone hydrochloride to give 0.17 g(96%) of an amide of type C (see scheme 1).

Rf (5/5 cyclohexane/EtOAc)=0.45

¹H NMR (CDCl₃, 400 MHz), 8.0 ppm (2H, m); 7.9 ppm (1H, m); 7.15 ppm (2H,m); 4.95 ppm (2H, d); 4.3 ppm (2H, q); 2.5 ppm (3H, s); 1.5 ppm (3H, t)

Step 8:

According to M11, 0.16 g (0.48 mmol) of the amide C (see scheme 1) isrefluxed with 0.287 g of iron and 0.048 ml of 36% HCl in anethanol/water mixture to give 0.08 g of the expected product D (seescheme 1).

m.p.: 174° C.

MS (ES⁺), m/z=287

¹H NMR (CDCl₃, 400 MHz) 8.0 ppm (2H, m); 7.15 ppm (2H, m), 6.7 ppm (1H,t); 4.5 ppm (2H, q); 4.1 ppm (2H, d); 2.4 ppm (3H, s); 1.5 ppm (3H, t)

Example 145-(3-Bromophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=3-bromophenyl)

Step 7:

According to M8, 0.08 g (0.4 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid is reacted with0.1 g (1 eq.) of 2-amino-3′-bromoacetophenone hydrochloride to give 0.16g (100%) of an amide of type C (see scheme 1).

Rf (98/2 CH₂Cl₂/MeOH)=0.29

¹H NMR (CDCl₃, 400 MHz), 8.15 ppm (1H, s); 7.9 ppm (2H, m); 7.8 ppm (1H,m); 7.4 ppm (1H, m); 5.0 ppm (2H, d); 4.3 ppm (2H, q); 2.6 ppm (3H, s);1.5 ppm (3H, t)

Step 8:

According to M11, 0.16 g (0.4 mmol) of the amide C is refluxed with 0.24g of iron and 0.04 ml of 36% HCl in an ethanol/water mixture to give0.06 g (43%) of the expected product D (see scheme).

m.p.: 173° C.

MS (ES⁺), m/z=348

¹H NMR (CDCl₃, 400 MHz), 8.1 ppm (1H, m); 7.9 ppm (1H, m), 7.6 ppm (1H,m), 7.4 ppm (1H, m), 7.25 ppm (1H, s), 6.3 ppm (1H, t); 4.6 ppm (2H, q);4.1 ppm (2H, d); 2.4 ppm (3H, s); 1.5 ppm (3H, t)

Example 153-Methyl-5-phenyl-1-propyl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=propyl; R3=phenyl)

Step 7:

According to M8, 0.37 g (1.6 mmol) of5-methyl-4-nitro-2-propyl-2H-pyrazole-3-carboxylic acid is reacted with0.28 g (1.6 mmol) of 2-aminoacetophenone hydrochloride to give 0.54 g(96%) of an amide of type C (see scheme 1).

Rf (90/10) CH₂Cl₂/acetone)=0.7

¹H NMR (CDCl₃, 400 MHz), 8.0 ppm (2H, d); 7.85 ppm (1H, t); 7.65 ppm(1H, m); 7.55 ppm (2H, m); 5.0 ppm (2H, d); 4.25 ppm (2H, t); 2.55 ppm(3H, s); 1.9 ppm (2H, m); 0.9 ppm (3H, t)

Step 8:

According to M11, 0.138 g (0.42 mmol) of the amide C (see scheme 1) isrefluxed with 0.28 g of iron and 0.05 ml of 36% HCl in an ethanol/watermixture to give 0.072 g (61%) of the expected product D (see scheme 1).

m.p.: 171° C.

MS (ES⁺), m/z=283

¹H NMR (CDCl₃, 400 MHz), 8.0 ppm (2H, d); 7.55 ppm (3H, m); 6.65 ppm(1H, t); 4.5 ppm (2H, t); 4.15 ppm (2H, d); 2.4 ppm (3H, s); 1.9 ppm(2H, m); 0.9 ppm (3H, t)

Example 161-(2-Hydroxyethyl)-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=2-hydroxyethyl; R3=phenyl)

Step 5:

6.3 g (33.8 mmol) of a pyrazole of type A4 (see scheme 1 and J. Org.Chem., 21, 833-835, 1956; Gazz. Chim. Ital., 75, 121-131, 1945) arereacted with 8.48 g (40.5 mmol) of 2-(2-bromoethoxy)tetrahydro-2H-pyran(commercial) to give 3.44 g (31%) of a pyrazole A5 (see scheme 1).

Rf (95/5 CH₂Cl₂/acetone)=0.47

¹H NMR (CDCl₃, 400 MHz), 4.55-4.35 ppm (5H, m); 4.0 ppm (1H, m); 3.7-3.4ppm (3H, m); 2.5 ppm (3H, s); 1.8-1.55 ppm (6H, m); 1.5 ppm (3H, t)

Step 6:

1.1 g (3.4 mmol) of the pyrazole A5 (see scheme 1) are reacted with 0.2g (5.1 mmol) of sodium hydroxide in a mixture of methanol and water togive 0.97 g (95%) of a pyrazole of type A (see scheme 1).

Rf (80/20 CH₂Cl₂/MeOH)=0.26

¹H NMR (CDCl₃, 400 MHz), 7.9 ppm (1H, s); 4.7-4.5 ppm (3H, m); 4.0 ppm(1H, m); 3.8-3.45 ppm (3H, m); 2.5 ppm 3H, s); 1.9-1.4 ppm (6H, m)

Step 7:

According to M8, 0.9 g (3 mmol) of2-(2-hydroxyethyle)-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid isreacted with 0.52 g (3 mmol) of 2-aminoacetophenone hydrochloride togive 1.43 g (100%, crude) of an amide of type C (see scheme 1).

Rf (90/10 CH₂Cl₂/acetone)=0.51

¹H NMR (CDCl₃, 400 MHz), 8.3 ppm (1H, s); 8.0 ppm (2H, m); 7.6 ppm (1H,m); 7.5 ppm (2H, m); 4.7 ppm (1H, m); 4.5 ppm (2H, t); 4.1 ppm (1H, m);3.85 ppm (1H, m); 3.7-3.4 ppm (2H, m); 2.55 ppm (3H, s); 1.9-1.4 ppm(6H, m)

Step 8:

According to M11, 1.4 g (3 mmol) of the amide C (see scheme 1) arerefluxed with 1.8 g of iron and 0.31 ml of 36% HCl in a mixture ofethanol and water to give 0.09 g (11%) of the expected product D (seescheme 1).

m.p.: 75° C.

MS (ES⁺), m/z=285

¹H NMR (CDCl₃, 400 MHz), 8.0 ppm (2H, m); 7.55 ppm (3H, m); 7.05 ppm(1H,t); 4.65 ppm (2H, t); 4.15 ppm (2H, d); 4.0 ppm (2H, m); 3.9 ppm(1H, OH); 2.4 ppm (3H, s).

Example 171-Ethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione

(R1=methyl; R2=ethyl; R3=phenyl)

Step 9:

0.2 g (0.74 mmol) of a pyrazolodiazepine of type D (see scheme 1), inwhich R1, R2 and R3 are as defined in this example, is refluxed intoluene with 0.6 g (2 eq.) of Lawesson's reagent to give 188 mg (89%) ofthe expected product E (see scheme 1).

m.p.: 203.5° C.

MS (ES⁺), m/z=285

¹H NMR (CDCl₃, 400 MHz), 8.0 ppm (2H, m); 7.8 ppm (1H, t), 7.5 ppm (3H,m); 4.8 ppm (2H, q); 4.25 ppm (2H, d); 2.5 ppm (3H, s); 1.6 ppm (3H, t)

Example 181-Ethyl-5-(3-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=3-methoxyphenyl)

Step 7:

According to M8, 0.5 g (2.51 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid is reacted with0.51 g (2.51 mmol) of 2-amino-3′-methoxyacetophenone hydrochloride(Patent, Brachwitz, Werner, DD65929, 1967) to give 0.8 g (92%) of anamide of type C (see scheme 1).

Rf (CH₂Cl₂/MeOH 90/10)=0.87

¹H NMR (CDCl₃, 400 MHz), 7.95 ppm (1H, s); 7.55 ppm (1H, m); 7.5 ppm(1H, m); 7.4 ppm (1H, m); 7.2 ppm (1H, m); 5.0 ppm (2H, d); 4.35 ppm(2H, q); 3.9 ppm (3H, s); 2.55 ppm (3H, s); 1.5 ppm (3H, t)

Step 8:

According to M11, 0.792 g (2.29 mmol) of the amide C (see scheme 1) isrefluxed with 1.37 g of iron and 0.23 ml of 36% aqueous HCl in anethanol/water mixture to give 0.312 g (46%) of the expected product D(see scheme 1).

m.p.: 120° C.

MS (ES⁺), m/z=299

¹H NMR (CDCl₃, 400 MHz), 7.6-7.3 ppm (3H, m); 7.0 ppm (1H, m); 6.9 ppm(1H,s); 4.6 ppm (2H, q); 4.1 ppm (2H, d); 3.9 ppm (3H, s); 2.4 ppm (3H,s); 1.5 ppm (3H, t)

Example 195-(2-Aminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=2-aminophenyl)

Step 7:

According to M8, 1.11 g (5.56 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid are reacted with0.5 g of 2-amino-2′-nitroacetophenone hydrochloride to give 0.246 g(44%) of an amide of type C (see scheme 1.

Rf (CH₂Cl₂/MeOH 90/10)=0.87

¹H NMR (CDCl₃, 400 MHz), 9.3 ppm (1H, s); 8.2 ppm (1H, m); 7.8 ppm (1H,m); 7.6-7.5 ppm (2H, m); 4.6 ppm (2H, d); 4.1 ppm (2H, q); 2.5 ppm (3H,s); 1.4 ppm (3H, t)

Step 8:

According to M11, 0.237 g (0.66 mmol) of the amide C (see scheme 1) isrefluxed with 0.4 g of iron and 0.07 ml of 36% HCl in an ethanol/watermixture to give 0.08 g (43%) of the expected product D (see scheme 1).

m.p.: 156° C.

MS (ES⁺), m/z=284

¹H NMR(CDCl₃, 400 MHz), 7.5 ppm (1H, m); 7.2 ppm (1H, m); 6.8-6.5 ppm(5H, m); 4.6 ppm (2H, q); 4.15 ppm (2H, d); 2.4 ppm (3H, s); 1.5 ppm(3H, t)

Example 201-Ethyl-5-(2-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=2-methoxyphenyl)

Step 7:

According to M8, 0.24 g (1.22 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid is reacted with0.245 g (1.22 mmol) of 2-amino-2′-methoxyoacetophenone hydrochloride (J.Org. Chem., 37, 2494-2496, 1972) to give 0.197 g (47%) of an amide oftype C (see scheme 1).

Rf (CH₂Cl₂/MeOH 95/5)=0.8

¹H NMR (CDCl₃, 400 MHz), 8.0 ppm (1H, m); 7.9 ppm (1H, CONH); 7.55 ppm(1H, m); 7.05 ppm (2H, m); 4.95 ppm (2H, d); 4.35 ppm (2H, q); 4.0 ppm(3H, s); 2.55 ppm (3H, s); 1.5 ppm (3H, t)

Step 8:

According to M8, 0.19 g (0.55 mmol) of the amide C (see scheme 1) isrefluxed with 0.33 g of iron and 0.055 ml of 36% HCl in an ethanol/watermixture to give 0.07 g (43%) of the expected product D (see scheme 1).

m.p.: 214° C.

MS (ES⁺), m/z: 299

¹H NMR (CDCl₃, 400 MHz), 7.75 ppm (1H, m); 7.4 ppm (1H, m); 7.1 ppm (1H,m); 7.0 ppm (1H, m); 6.45 ppm (1H,s); 4.6 ppm (2H, q); 4.0 ppm (2H, d);3.9 ppm (3H, s); 2.4 ppm (3H, s); 1.5 ppm (3H, t)

Example 213-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=tert-butyl; R2=ethyl; R3=phenyl)

Step 3:

According to M1, 9 g (46 mmol) of ethyl5-tert-butyl-2H-pyrazole-3-carboxylate and 11.61 g of NaNO₃ are reactedin 90 ml of concentrated H₂SO₄ to give 4.5 g (41%, white powder) of acompound of type A4 (see scheme 1).

MS (ES−), m/z=240

Rf (CH₂Cl₂/acetone 90/10)=0.54

Step 5:

According to M5, 4.8 g (19.8 mmol) of compound A7 (see scheme 1) arereacted with 1.74 ml (22 mmol) of iodoethane to give 4 g of a compoundof type A5 (see Scheme 1) (yellow oil, 75%).

MS (ES+), m/z=270

¹H NMR (CDCl₃, 400 MHz), 1.35 ppm (12H, m); 1.4 ppm (3H, t); 4.35 ppm(4H, q)

Step 6:

4 g (14.8 mmol) of compound A5 (see scheme 1) are reacted with 0.89 g(22 mmol) of sodium hydroxide dissolved in a methanol/water mixture togive 3.2 g of a compound of type A (see scheme 1)(white powder, 89%)

MS (ES−), m/z=240

¹H NMR (DMSO, 400 MHz), 1.05 ppm (9H, s); 1.1 ppm (3H, t); 4.05 ppm (2H,q); 14.4 ppm (1H, m)

Step 7:

According to M8, 1 g (4.1 mmol) of compound A (see scheme 1) is reactedwith 0.7 g of 2-amino-acetophenone hydrochloride to give 1.3 g (88%) ofa compound of type C (see scheme 1).

MS (ES+), m/z=359

¹H NMR (CDCl₃, 400 MHz) 1.45 ppm (9H, s); 1.5 ppm (3H, t); 4.2 ppm (2H,q); 4.95 ppm (2H, d); 7.4 ppm (1H, m); 7.55 ppm (2H, m); 7.65 ppm (1H,t); 8.0 ppm (2H, d)

Step 8:

According to M11, 1.3 g (3.6 mmol) of compound C (see scheme 1) arerefluxed with 0.5 ml of HCl and 2.16 g of iron in an ethanol/watermixture to give 0.2 g (18%) of the expected product D (see scheme 1).

MS (ES+), m/z=311

m.p.=160° C.

¹H NMR (CDCl₃, 400 MHz), 1.5 ppm (12H, m); 4.1 ppm (2H, d); 4.55 ppm(2H, q); 6.7 ppm (1H, m); 7.45 ppm (3H, m); 8.0 ppm (2H, d)

Example 223-Methyl-5-phenyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione

(R1=methyl; R2=propyl; R3=phenyl)

Step 9:

0.57 g (2 mmol) of3-Methyl-5-phenyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-oneis refluxed in toluene with 1.6 g (4 mmol) of Lawesson's reagent to give0.58 g (97%) of a compound of type E (see scheme 1).

MS (ES+), m/z=299

¹H NMR (CDCl₃, 400 MHz) 0.9 ppm (3H, t); 1.95 ppm (2H, m); 2.4 ppm (3H,s); 4.2 ppm (2H, m); 4.75 ppm (2H, t); 7.4 ppm (3H, m); 7.95 ppm (2H,d); 8.65 ppm (1H, m)

m.p.: 156° C.

Example 231-Ethyl-3-methyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=p-tolyl)

Step 7:

According to M8, 0.31 g (1.56 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid is reacted with0.29 g (1.56 mmol) of 2-amino-4′-methylacetophenone hydrochloride togive 0.5 g (98%) of an amide of type C (see scheme 1).

Rf (CH₂Cl₂/MeOH 90/10)=0.85

¹H NMR(CDCl₃, 400 MHz), 7.9 ppm (3H, m); 7.3 ppm (2H, m); 4.95 ppm (2H,d); 4.35 ppm (2H, q); 2.55 ppm (3H, 9); 2.45 ppm (3H, s); 1.5 ppm (3H,t)

Step 8:

According to M11, 0.5 g (1.51 mmol) of the amide C (see scheme 1) isrefluxed with 0.94 g of iron and 0.17 ml of 36% HCl in an ethanol/watermixture to give 0.15 g (34%) of the expected product D (see scheme 1).

m.p.: 185° C.

MS (ES⁺), m/z=283

¹H NMR (CDCl₃, 400 MHz), 7.9 ppm (2H, d); 7.25 ppm (2H, d); 6.5 ppm (1H,s); 4.6 ppm (2H, q); 4.1 ppm (2H, d); 2.4 ppm (6H, s); 1.5 ppm (3H, t)

Example 245-(3-Aminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=3-aminophenyl)

Step 7:

According to M8, 0.92 g (4.62 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid is reacted with 1g (4.62 mmol) of 2-amino-3′-nitroacetophenone hydrochloride to give 1.3g (78%) of an amide of type C (see scheme 1).

Rf (CH₂Cl₂/MeOH 90/10)=0.89

¹H NMR (CDCl₃, 400 MHz), 9.1 ppm (1H, s); 8.8 ppm (1H, s); 8.4 ppm (1H,m); 8.5 ppm (1H, m); 7.8 ppm (1H, m); 4.95 ppm (2H, d); 4.3 ppm (2H, q);2.5 ppm (3H, s); 1.5 ppm (3H, t)

Step 8:

According to M11, 1.3 g (3.6 mmol) of the amide C (see scheme 1) arerefluxed with 2.15 g of iron and 0.38 ml of 36% HCl in an ethanol/watermixture to give 0.34 g (34%) of the expected product D (see scheme 1).

m.p.: 80° C.

MS (ES⁺), m/z=284

¹H NMR (CDCl₃, 400 MHz), 7.35 ppm (1H, m); 7.2 ppm (2H, m); 6.8 ppm(2H,m); 4.6 ppm (2H, q); 4.05 ppm (2H, d); 3.8 ppm (2H, bs); 2.4 ppm(3H, s); 1.5 ppm (3H, t)

Example 253-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione

(R1=tert-butyl; R2=ethyl; R3=phenyl)

Step 9:

0.37 g (2.2 mmol) of3-tert-butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-oneis reacted with 0.96 g (4.4 mmol) of Lawesson's reagent to give 0.25 gof a yellow powder (66%).

MS (ES+), m/z=327

m.p.=230° C.

¹H NMR (CDCl₃, 400 MHz) 1.45 ppm (9H, s); 1.5 ppm (3H, m); 4.2 ppm (2H,m); 4.8 ppm (2H, q); 7.45 ppm (3H, m); 8.0 ppm (2H, d); 8.55 ppm (1H,m).

Example 265-(4-Aminophenyl)-3-tert-butyl-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=tert-butyl; R2=ethyl; R3=4-aminophenyl)

Step 7:

According to M8, 1.2 g (4.9 mmol) of5-tert-butyl-2-ethyl-4-nitro-2H-pyrazole-3-carboxylic acid are reactedwith 1.06 g of 2-amino-4′-nitroacetophenone hydrochloride to give 1.15 g(58%) of an amide of type C (see scheme 1).

MS (ES−), m/z=402

¹H NMR (CDCl₃, 400 MHz), 1.4 ppm (9H, s); 1.5 ppm (3H, t); 4.25 ppm (2H,q); 4.95 ppm (2H, d); 7.4 ppm (1H, m); 8.15 ppm (2H, d); 8.35 ppm (2H,d)

Step 8:

According to M11, 1.15 g (2.8 mmol) of the amide C (see scheme 1) arerefluxed with 0.5 ml of HCl and 1.7 g of iron in an ethanol/watermixture to give 0.43 g (48%) of the expected compound D (see scheme 1).

MS (ES+), m/z=326

m.p.=189° C.

¹H NMR (CDCl₃, 400 MHz), 1.45 ppm (12H, m); 3.95 ppm (2H, s); 4.05 ppm(2H, d); 4.5 ppm (2H, q); 6.2 ppm (1H, m); 6.65 ppm (2H, d); 7.8 ppm(2H, d)

Example 275-(4-Aminophenyl)-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=isopropyl; R2=ethyl; R3=4-aminophenyl)

Step 7:

According to M8, 1.3 g (4.9 mmol) of2-ethyl-5-isopropyl-4-nitro-2H-pyrazole-3-carboxylic acid are reactedwith 1.23 g of 2-amino-4′-nitro-acetophenone hydrochloride to give 2 g(90%) of the amide of type C (see scheme 1).

MS (ES−), m/z=388

¹H NMR (CDCl₃, 400 MHz), 1.3 ppm (9H, s); 1.5 ppm (3H, t); 3.55 ppm (1H,q); 4.3 ppm (2H, q); 5 ppm (2H, d); 7.8 ppm (1H, m); 8.15 ppm (2H, d);8.4 ppm (2H, d)

Step 8:

According to M11, 2 g (5.1 mmol) of the amide C (see scheme 1) arerefluxed with 0.5 ml of HCl and 3.07 g of iron in an ethanol/watermixture to give 0.5 g (31%) of the compound of type D (see scheme 1).

MS (ES+), m/z=312

m.p.=191° C.

¹H NMR (DMSO, 400 MHz), 1.15 ppm (6H, m); 1.25 ppm (3H, m); 3.05 ppm(1H, q); 3.8 ppm (2H, d); 4.3 ppm (2H, q); 5.65 ppm (2H, m); 6.5 ppm(2H, d); 7.6 ppm (2H, d); 8 ppm (1H, m)

Example 281-Ethyl-5-(4-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=4-hydroxyphenyl)

17 ml of a molar solution of BBr₃ in dichloromethane are added dropwiseto a solution of 0.2 g of1-ethyl-5-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-onein 84 ml of dichloromethane. The resulting mixture is refluxed for 6hours. After cooling to RT, the reaction medium is neutralized withsodium bicarbonate solution. The organic phase is dried and evaporated.The product is purified by flash chromatography (gradient: CH₂Cl₂, 90/10CH₂Cl₂/acetone, 80/20 CH₂Cl₂/acetone). Evaporation of the solvent gives0.103 g of compound D in the form of a beige powder (54%).

Rf (90/10 CH₂Cl₂/MeOH)=0.25

¹H NMR (DMSO, 400 MHz), 9.5 ppm (1H, OH); 7.9 ppm (2H, m); 7.8 ppm (1H,bs); 6.9 ppm (2H, m); 4.5 ppm (2H, q); 4 ppm (2H, d); 2.4 ppm (3H, s);1.5 ppm (3H, t)

MS (ES+) m/z=285

m.p.=250° C.

Example 295-(4-Aminophenyl)-3-methyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=propyl; R3=4-aminophenyl)

Step 7:

According to M8, 1.5 g (7 mmol) of5-methyl-4-nitro-2-propyl-2H-pyrazole-3-carboxylic acid (A) are reactedwith 1.52 g (7 mmol) of 2-amino-4′-nitro-acetophenone hydrochloride togive 2.5 g (95%) of an amide of type C (see scheme 1).

Rf (5/5 cyclohexane/ethyl acetate)=0.5

¹H NMR (CDCl₃, 400 MHz), 8.4 ppm (2H, d); 8.2 ppm (2H, d); 8 ppm (1H,m); 5 ppm (2H, d); 4.25 ppm (2H, t); 2.55 ppm (3H, s); 1.9 ppm (2H, m);0.95 ppm (3H, t)

Step 8:

According to M11, 2.5 g (6.7 mmol) of the amide C (see scheme 1) arerefluxed with 4.1 g of iron and 0.83 ml of 36% HCl in an ethanol/watermixture to give 0.75 g (40%) of the expected product D (see scheme 1).

m.p.: 225° C.

MS (ES+), m/z=298

¹H NMR (CDCl₃, 400 MHz), 7.9 ppm (1H, m); 7.8 ppm (2H, d); 6.7 ppm (2H,d); 4.9 ppm (2H, s); 4.45 ppm (2H, t); 4 ppm (2H, d); 2.35 ppm (3H, s);1.85 ppm (2H, m); 0.9 ppm (3H, t)

Example 303-Methyl-5-phenyl-1-(2.2.2-trifluoroethyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=2,2,2-trifluoroethyl; R3=phenyl)

Step 7:

According to M8, 0.8 g (3.2 mmol) of5-methyl-4-nitro-2-(2,2,2-trifluoroethyl)-2H-pyrazole-3-carboxylic acid(A) is reacted with 0.54 g (3.2 mmol) of 2-aminoacetophenonehydrochloride to give 0.14 g (12%) of an amide of type C (see scheme 1).

Rf (cyclohexane/EtOAc 5/5)=0.76

MS (ES+), m/z=371

¹H NMR (CDCl₃, 400 MHz), 8.5 ppm (1H, s); 8.0 ppm (2H, d); 7.7 ppm (1H,m); 7.55 ppm (2H, m); 5.2 ppm (2H, m); 5.0 ppm (2H, d); 2.6 ppm (3H, s)

Step 8:

According to M11, 0.14 g (0.38 mmol) of the amide C (see scheme 1) isrefluxed with 0.23 g of iron and 0.046 ml of 36% HCl in an ethanol/watermixture to give 0.1 g (80.5%) of the expected product D (see scheme 1).

MS (ES+), m/z=323

¹H NMR (CDCl₃, 400 MHz), 9.0 ppm (2H, m); 7.5 ppm (3H, m); 6.6 ppm (1H,t); 5.3 ppm (2H, m); 4.2 ppm (2H, d); 2.5 ppm (3H, s)

Example 315-Cyclohexyl-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=cyclohexyl)

Synthesis of the α-amino ketone:

According to M6, 2.7 g (13.2 mmol) of 2-bromo-1-cyclohexylethanone(Tetrahedron, 48, 1, 67-78, 1992) are mixed with 1.92 g (13.7 mmol) ofhexamethylenetetramine in 20 ml of chloroform. The mixture is heated at48° C. for 4 hours and then evaporated to dryness. The residue is takenup in 20 ml of ethanol and 9 ml of 36% hydrochloric acid. After leavingovernight at room temperature, the reaction medium is filtered. Thefiltrate is evaporated to dryness to give an oil which is crystallizedfrom diethyl ether. After filtration and drying, 2.08 g (80%) of2-amino-1-cyclohexylethanone hydrochloride are obtained in the form of apaste.

MS (ES+), m/z=141

Rf (80/20 CH₂Cl₂/MeOH): 0.31

Step 7:

According to M8, 1.8 g (8.9 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) are reactedwith 1.6 g (8.9 mmol) of 2-amino-1-cyclohexylethanone hydrochloride togive 1.15 g (40%) of an amide of type C (see scheme 1).

Rf (CH₂Cl₂/MeOH 95/5)=0.48

¹H NMR (CDCl₃, 400 MHz), 7.6 ppm (1H, bs); 4.4 ppm (2H, d); 4.3 ppm (2H,q); 2.5 ppm (3H, s); 2.4 ppm (1H, m); 2.0 to 1.3 ppm (13H, m)

Step 8:

According to M11, 0.65 g (2 mmol) of the amide C (see scheme 1) isrefluxed with 1.2 g of iron and 0.2 ml of 36% HCl in an ethanol/watermixture to give 0.35 g (64%) of the expected product D (see scheme 1).

m.p.: 50° C.

MS (ES+), m/z=275

¹H NMR (C₆D₆, 400 MHz), 6.6 ppm (1H, t); 4.6 ppm (2H, q); 3.6 ppm (2H,d); 2.5 ppm (1H, td); 2.4 ppm (3H, s); 1.9 to 1.3 ppm (1OH, m); 1.5 ppm(3H, t)

Example 321-Ethyl-3-methyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=4-pyridyl)

Step 7:

According to M8, 1.24 g (6.2 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) are reactedwith 1.3 g (6.2 mmol) of 2-amino-1-pyrid-4-yl-ethanone hydrochloride (J.Med. Chem., 38, 17, 3342-3350, 1995; J. Amer. Chem. Soc., 67, 1468-1472,1945) to give 0.77 g (39%) of an amide of type C (see scheme 1).

Rf (80/20 CH₂Cl₂/acetone)=0.39

¹H NMR (DMSO, 400 MHz), 9.4 ppm (1H, t); 8.7 ppm (2H, d); 7.8 ppm (2H,d); 4.8 ppm (2H, d); 4.1 ppm (2H, q); 2.3 ppm (3H, s); 1.2 ppm (3H, t)

Step 8:

According to M11, 0.76 g (2.4 mmol) of the amide C (see scheme 1) isrefluxed with 1.43 g of iron and 0.24 ml of 36% HCl in an ethanol/watermixture to give 0.1 g (15%) of the expected product D (see scheme 1).

m.p.: 148° C.

MS (ES+), m/z=270

¹H NMR (CDCl₃, 400 MHz), 8.8 ppm (2H, d); 8.3 ppm (1H, t); 7.9 ppm (2H,d); 4.4 ppm (2H, q); 4.1 ppm (2H, d); 2.3 ppm (3H, s); 1.4 ppm (3H, t)

Example 335-tert-Butyl-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=tert-butyl)

Step 7:

According to M8, 0.66 g (3.3 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) is reactedwith 0.5 g (3.3 mmol) of 1-amino-3,3-dimethyl-butan-2-one hydrochloride(J. Org. Chem., 53, 5, 1113-1114, 1988) to give 0.72 g (73.5%) of anamide of type C (see scheme 1).

Rf (90/10 CH₂Cl₂/MeOH)=0.88

¹H NMR (CDCl₃, 400 MHz), 7.6 ppm (1H, bs); 4.5 ppm (2H, d); 4.3 ppm (2H,q); 2.6 ppm (3H, s); 1.5 ppm (3H, t); 1.3 ppm (9H, s)

Step 8:

According to M11, 0.71 g (2.4 mmol) of the amide C (see scheme 1) isrefluxed with 1.43 g of iron and 0.24 ml of 36% HCl in an ethanol/watermixture to give 0.27 g (46%) of the expected product D (see scheme 1).

m.p.: 120° C.

MS (ES+), m/z=249

¹H NMR (CDCl₃, 400 MHz), 6.6 ppm (1H, t); 4.5 ppm (2H, q); 3.7 ppm (2H,d); 2.3 ppm (3H, s); 1.4 ppm (3H, t); 1.2 ppm (9H, s)

Example 343-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=butyl; R2=ethyl; R3=phenyl)

Step 7:

According to M8, 1 g (4.1 mmol) of5-butyl-2-ethyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) is reactedwith 0.7 g (4.1 mmol) of 2-aminoacetophenone hydrochloride to give 1.25g (86%) of an amide of type C (see scheme 1).

MS (ES+), m/z=359

¹H NMR (CDCl₃, 400 MHz), 8.0 ppm (2H, d); 7.8 ppm (1H, bs); 7.7 ppm (1H,m); 7.5 ppm (2H, m); 5.0 ppm (2H, d); 4.3 ppm (2H, q); 3.0 ppm (2H, m);1.7 ppm (2H, m); 1.5 ppm (5H, m); 1.0 ppm (3H, t)

Step 8:

According to M11, 1.25 g (3.5 mmol) of the amide C (see scheme 1) arerefluxed with 2.1 g of iron and 0.5 ml of 36% HCl in an ethanol/watermixture to give the expected product D (see scheme 1).

m.p.: 105.4° C.

MS (ES+), m/z=311

¹H NMR (CDCl₃, 400 MHz), 8.0 ppm (2H, m); 7.5 ppm (3H, m); 4.6 ppm (2H,q); 4.1 ppm (2H, d); 2.8 ppm (2H, m); 1.9 to 1.2 ppm (7H, m); 1.0 ppm(3H, t)

Example 355-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=isopropyl; R2=ethyl; R3=tert-butyl)

Step 7:

According to M9, 0.4 g (1.76 mmol) of2-ethyl-5-isopropyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) is reactedwith 0.266 g (1.76 mmol) of 1-amino-3,3-dimethylbutan-2-onehydrochloride (J. Org. Chem., 53, 5, 1113-1114, 1988) to give 0.38 g(67%) of an amide of type C (see scheme 1).

MS (ES+), m/z=325

Step 8:

According to M12, 0.38 g (1.17 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 1.32 g (5 eq.) of tin chloride dihydrate togive 0.22 g (68%) of the expected product D (see scheme 1).

MS (ES+), m/z=277

¹H NMR (DMSO, 400 MHz), 8.2 ppm (1H, t); 4.4 ppm (2H, q); 3.6 ppm (2H,d); 3.1 ppm (1H, m); 1.3 ppm (3H, t); 1.25 ppm (6H, d); 1.2 ppm (9H, s)

Example 361-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=isopropyl; R2=ethyl; R3=p-tolyl)

Step 7:

According to M9, 0.4 g (1.76 mmol) of2-ethyl-5-isopropyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) is reactedwith 0.327 g (1.76 mmol) of 2-amino-1-p-tolylethanone hydrochloride togive 0.32 g (51%) of an amide of type C (see scheme 1).

MS (ES+), m/z=359

¹H NMR (CDCl₃, 400 MHz), 7.9 ppm (2H, d); 7.7 ppm (1H, bs); 7.3 ppm (2H,d); 5.0 ppm (2H, d); 4.3 ppm (2H, q); 3.6 ppm (1H, m); 2.4 ppm (3H, s);1.5 ppm (3H, t); 1.3 ppm (6H, d)

Step 8:

According to M12, 0.32 g (1.17 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 1.01 g of tin chloride dihydrate to give 0.13 g(47%) of the expected product D (see scheme 1).

MS (ES+), m/z=311

¹H NMR (DMSO, 400 MHz), 8.2 ppm (1H, t); 7.9 ppm (2H, d); 7.3 ppm (2H,d); 4.4 ppm (2H, q); 4.0 ppm (2H, d); 3.2 ppm (1H, m); 2.3 ppm (3H, s);1.3 ppm (3H, t); 1.2 ppm (6H, d)

Example 374-(1-Ethyl-3-isopropyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile

(R1=isopropyl; R2=ethyl; R3=4-cyanophenyl)

Step 7:

According to M9, 0.4 g (1.76 mmol) of2-ethyl-5-isopropyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) is reactedwith 0.346 g (1.76 mmol) of 4-(2-aminoethanoyl)benzonitrilehydrochloride (Yakugaku Zasshi, 72, 305-307, 1952) to give 0.27 g (41%)of an amide of type C (see scheme 1).

MS (ES−), m/z=368

¹H NMR (CDCl₃, 400 MHz), 8.1 ppm (2H, d); 7.8 ppm (2H, d); 7.75 ppm (1H,bs); 5.0 ppm (2H, d); 4.3 ppm (2H, m); 3.5 ppm (1H, m); 1.5 ppm (3H, m);1.3 ppm (6H, m)

Step 8:

According to M12, 0.27 g (0.7 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 0.82 g of tin chloride dihydrate to give 0.077g (33%) of the expected product D (see scheme 1)

MS (ES+), m/z=322

¹H NMR (CDCl₃, 400 MHz),

8.3 ppm (1H, t); 8.2 ppm (2H, m); 8.0 ppm (2H, m); 4.45 ppm (2H, q);4.05 ppm (2H, m); 3.2 ppm (1H, m); 1.4 ppm (3H, t); 1.3 ppm (6H, d)

Example 381-Ethyl-3-isopropyl-5-(4-pyrrolidin-1-yl-phenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,

(R1=isopropyl; R2=ethyl; R3=4-(1-pyrrolidyl)phenyl

Synthesis of the α-amino ketone B with R3=4-(1-pyrrolidinyl)phenyl:

According to M6, 16.1 g (60 mmol) of2-bromo-1-(4-(1-pyrrolidinyl)phenyl)ethanone are mixed with 8.75 g (62.4mmol) of hexamethylenetetramine in 240 ml of chloroform. The mixture isheated at 48° C. for 4 hours and then filtered at room temperature. Theprecipitate is taken up in 88 ml of ethanol and 44 ml of 36%hydrochloric acid. After stirring overnight at room temperature, thereaction medium is filtered. The filtrate is evaporated to dryness togive an oil which is crystallized from ethanol. After filtration,washing of the precipitate with 20 ml of water and drying, 6.3 g (43%)of 2-amino-1-(4-(1-pyrrolidine)phenyl)-ethanone hydrochloride areobtained in the form of a beige powder containing 3% by weight of NH₄Cl.

¹H NMR (DMSO, 400 MHz), 8.1 ppm (3H, s); 7.65 ppm (2H, d); 6.45 ppm (2H,d); 4.2 ppm (2H, m); 3.2 ppm (4H, m); 1.8 ppm (4H, t)

Step 7:

According to M9, 0.4 g (1.76 mmol) of2-ethyl-5-isopropyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) is reactedwith 0.437 g (1.76 mmol) of 2-amino-1-(4-(1-pyrrolidine)phenyl)-ethanonehydrochloride (97%) to give 0.36 g (49%) of an amide of type C (seescheme 1).

MS (ES+), m/z=414

Step 8:

According to M12, 0.36 g (0.87 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 0.98 g (5 eq.) of tin chloride dihydrate togive 0.143 g (45%) of the expected product D (see scheme 1).

MS (ES+), m/z=366

¹H NMR (DMSO, 400 MHz), 8.2 ppm (1H, t); 7.9 ppm (2H, d); 6.6 ppm (2H,d); 4.4 ppm (2H, q); 3.95 ppm (2H, d); 3.3 ppm (4H, m); 3.2 ppm (1H, m);2 ppm (4H, m); 1.35 ppm (3H, t); 1.3 ppm (6H, d)

Example 395-(2,4-Dimethoxyphenyl)-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=isopropyl; R2=ethyl; R3=2,4-dimethoxyphenyl)

Step 7:

According to M9, 0.4 g (1.76 mmol) of2-ethyl-5-isopropyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) is reactedwith 0.408 g (1.76 mmol) of 2-amino-1-(2,4-dimethoxyphenyl)-ethanonehydrochloride to give 0.47 g (66%) of an amide of type C (see scheme 1).

MS (ES+), m/z=40

Step 8:

According to M12, 0.47 g (1.16 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 1.31 g of tin chloride dihydrate to give 0.152g (37%) of the expected product D (see scheme 1).

MS (ES+), m/z=357

¹H NMR (DMSO, 400 MHz), 8.3 ppm (1H, t); 7.6 ppm (1H, d); 6.7 ppm (2H,m); 4.45 ppm (2H, q); 3.9 ppm (3H, s); 3.85 ppm (2H,d); 3.8 ppm (3H, s);3.2 ppm (1H, m); 1.4 ppm (3H, t); 1.2 ppm (6H, d)

Example 405-tert-Butyl-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=isopropyl; R2=propyl; R3=tert-butyl)

Step 7:

According to M9, 0.425 g (1.76 mmol) of5-isopropyl-4-nitro-2-propyl-2H-pyrazole-3-carboxylic acid (A) isreacted with 0.267 g (1.76 mmol) of 1-amino-3,3-dimethylbutan-2-onehydrochloride (J. Org. Chem., 53, 5, 1113-1114, 1988) to give 0.43 g(72%) of an amide of type C (see Scheme 1).

MS (ES+), m/z=33

Step 8:

According to M12, 0.43 g (1.27 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 1.43 g of tin chloride dihydrate to give 0.236g (64%) of the expected product D (see Scheme 1).

MS (ES+), m/z=291

¹H NMR (DMSO, 400 MHz), 8.25 ppm (1H, bs); 4.4 ppm (2H, bs); 3.6 ppm(2H, s); 3.2 ppm (1H, m); 1.8 ppm (2H, m); 1.3 ppm (6H, d); 1.25 ppm(9H, s); 0.85 ppm (3H, t)

Example 413-Isopropyl-1-propyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=isopropyl; R2=propyl; R3=p-tolyl)

Step 7:

According to M9, 0.425 g (1.76 mmol) of5-isopropyl-4-nitro-2-propyl-2H-pyrazole-3-carboxylic acid (A) isreacted with 0.327 g (1.76 mmol) of 2-amino-1-p-tolylethanonehydrochloride to give 0.37 g (57%) of an amide of type C (see scheme 1).

MS (ES+), m/z=373

Step 8:

According to M12, 0.37 g (1 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 1.12 g of tin chloride dihydrate to give 0.176g (55%) of the expected product D (see scheme 1).

MS (ES+), m/z=325

¹H NMR (DMSO, 400 MHz), 8.1 ppm (1H, t); 7.7 ppm (2H, d); 7.1 ppm (2H,d); 4.25 ppm (2H, t); 3.8 ppm (2H, d); 3.1 ppm (1H, m); 2.2 ppm (3H, s);1.6 ppm (2H, m); 1.1 ppm (6H, d); 0.7 ppm (3H, t)

Example 424-(3-Isopropyl-8-oxo-1-propyl-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile

(R1=isopropyl; R2=propyl; R3=4-cyanophenyl)

Step 7:

According to M9, 0.425 g (1.76 mmol) of5-isopropyl-4-nitro-2-propyl-2H-pyrazole-3-carboxylic acid (A) isreacted with 0.346 g (1.76 mmol) of 4-(2-aminoethanoyl)benzonitrilehydrochloride (Yakugaku Zasshi, 72, 305-307, 1952) to give 0.32 g (48%)of an amide of type C (see Scheme 1).

MS (ES+), m/z=384

¹H NMR (CDCl₃, 400 MHz), 8.1 ppm (2H, d); 7.85 ppm (2H, d); 7.7 ppm (1H,bs); 5.0 ppm (2H, d); 4.3 ppm (2H, m); 3.6 ppm (1H, m); 1.9 ppm (2H, m);1.3 ppm (6H, d); 0.9 ppm (3H, m)

Step 8:

According to M12, 0.32 g (0.834 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 0.94 g of tin chloride to give 0.076 g (27%) ofthe expected product D (see Scheme 1).

MS (ES+), m/z=336

¹H NMR (DMSO, 400 MHz), 8.3 ppm (1H, bs); 8.15 ppm (2H, m); 8.0 ppm (2H,m); 4.4 ppm (2H, q); 4.05 ppm (2H, m); 3.2 ppm (1H, m); 1.8 ppm (2H, m);1.3 ppm (6H, d); 0.9 ppm (3H, t)

Example 435-(2,4-Dimethoxyphenyl)-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=isopropyl; R2=propyl; R3=2,4-dimethoxyphenyl)

Step 7:

According to M9, 0.425 g (1.76 mmol) of5-isopropyl-4-nitro-2-propyl-2H-pyrazole-3-carboxylic acid (A) isreacted with 0.407 g (1.76 mmol) of2-amino-1-(2,4-dimethoxy-phenyl)ethanone hydrochloride to give 0.54 g(73%) of an amide of type C (see Scheme 1).

MS (ES+), m/z=41

Step 8:

According to M12, 0.54 g (1.29 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 1.46 g (5 eq.) of tin chloride dihydrate togive 0.246 g (51%) of the expected product D (see Scheme 1).

MS (ES+), m/z=371

¹H NMR (DMSO, 400 MHz), 8.3 ppm (1H, bs); 7.55 ppm (1H, m); 6.7 ppm (2H,m); 4.4 ppm (2H, t); 3.9 ppm (3H, s); 3.8 ppm (5H, m); 3.2 ppm (1H, m);1.8 ppm (2H, m); 1.3 ppm (6H, m); 0.8 ppm (3H, m)

Example 443,5-Di-tert-butyl-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=tert-butyl; R2=ethyl; R3=tert-butyl)

Step 7:

According to M9, 0.425 g (1.76 mmol) of5-tert-butyl-2-ethyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) isreacted with 0.267 g (1.76 mmol) of 1-amino-3,3-dimethylbutan-2-onehydrochloride to give 0.37 g (62%) of an amide of type C (see Scheme 1).

MS (ES+), m/z=339

Step 8:

According to M12, 0.37 g (1.09 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 1.23 g of tin chloride dihydrate to give 0.17 g(54%) of the expected product D (see Scheme 1).

MS (ES+), m/z=291

¹H NMR (DMSO, 400 MHz), 8.2 ppm (1H, t); 4.4 ppm (2H, q); 3.5 ppm (2H,d); 1.35 ppm (9H, s); 1.3 ppm (3H, t); 1.2 ppm (9H, s)

Example 453-tert-Butyl-1-ethyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=tert-butyl; R2=ethyl; R3=p-tolyl)

Step 7:

According to M9, 0.425 g (1.76 mmol) of5-tert-butyl-2-ethyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) isreacted with 0.327 g (1.76 mmol) of 2-amino-1-p-tolylethanonehydrochloride to give 0.39 g (60%) of an amide of type C (see Scheme 1).

MS (ES+), m/z=373

Step 8:

According to M12, 0.39 g (1.05 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 1.18 g of tin chloride dihydrate to give 0.181g (53%) of the expected product D (see Scheme 1).

MS (ES+), m/z=325

¹H NMR (DMSO, 400 MHz), 8.25 ppm (1H, t); 7.9 ppm (2H, d); 7.3 ppm (2H,d); 4.4 ppm (2H, q); 4.0 ppm (2H, d); 2.35 ppm (3H, s); 1.4 ppm (9H, s);1.35 ppm (3H, t)

Example 464-(3-tert-Butyl-1-ethyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile

(R1=tert-butyl; R2=ethyl; R3=4-cyanophenyl)

Step 7:

According to M9, 0.425 g (1.76 mmol) of5-tert-butyl-2-ethyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) isreacted with 0.346 g (1.76 mmol) of 4-(2-aminoethanoyl)benzonitrilehydrochloride (Yakugaku Zasshi, 72, 305-307, 1952) to give 0.33 g (49%)of an amide of type C (see scheme 1).

MS (ES+), m/z=384

¹H NMR (CDCl₃, 400 MHz), 8.1 ppm (2H, d); 7.8 ppm (2H, d); 5.0 ppm (2H,d); 4.3 ppm (2H, m); 1.5 to 1.4 ppm (12H, m)

Step 8:

According to M12, 0.33 g (0.86 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 0.97 g of tin chloride dihydrate to give 0.091g (32%) of the expected product D (see Scheme 1).

MS (ES+), m/z=336

¹H NMR (DMSO, 400 MHz), 8.3 ppm (1H, t); 8.2 ppm (2H, d); 8.0 ppm (2H,d); 4.45 ppm (2H, m); 4.0 ppm (2H, d); 1.4 ppm (9H, s); 1.35 ppm (3H, t)

Example 473-tert-Butyl-5-(2,4-dimethoxyphenyl)-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=tert-butyl; R2=ethyl; R3=2,4-dimethoxyphenyl)

Step 7:

According to M9, 0.425 g (1.76 mmol) of5-tert-butyl-2-ethyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) isreacted with 0.407 g (1.76 mmol) of2-amino-1-(2,4-dimethoxyphenyl)ethanone hydrochloride (J. Chem. Res.Miniprint, 7, 1581-1597, 1989) to give 0.56 g (76%) of an amide of typeC (see Scheme 1).

MS (ES+), m/z=419

Step 8:

According to M12, 0.56 g (1.34 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 1.51 g of tin chloride dihydrate to give 0.112g (23%) of the expected product D (see Scheme 1).

MS (ES+), m/z=371

¹H NMR (DMSO, 400 MHz), 8.2 ppm (1H, t); 7.4 ppm (1H, s); 6.5 ppm (2H,m); 4.3 ppm (2H, m); 3.75 ppm (3H, s); 3.65 ppm (5H, bs); 1.2 ppm (9H,s); 1.15 ppm (3H, t)

Example 483,5-Di-tert-butyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=tert-butyl; R2=propyl; R3=tert-butyl)

Step 7:

According to M9, 0.449 g (1.76 mmol) of5-tert-butyl-2-ethyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) isreacted with 0.267 g (1.76 mmol) of 1-amino-3,3-dimethylbutan-2-onehydrochloride (J. Org. Chem., 53, 5, 1113-1114, 1988) to give 0.42 g(68%) of an amide of type C (see scheme 1).

MS (ES+), m/z=353

Step 8:

According to M12, 0.42 g (1.2 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 1.34 g of tin chloride dihydrate to give 0.154g (42%) of the expected product D (see Scheme 1).

MS (ES+), m/z=305

¹H NMR (DMSO, 400 MHz), 8.2 ppm (1H, t); 4.3 ppm (2H, t); 3.55 ppm (2H,d); 1.7 ppm (2H, m); 1.4 ppm (9H, s); 1.2 ppm (9H, s); 0.8 ppm (3H, t)

Example 493-tert-Butyl-1-propyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=tert-butyl; R2=propyl; R3=p-tolyl)

Step 7:

According to M9, 0.449 g (1.76 mmol) of5-tert-butyl-4-nitro-2-propyl-2H-pyrazole-3-carboxylic acid (A) isreacted with 0.327 g (1.76 mmol) of2-amino-1-p-tolylethanonehydrochloride to give 0.43 g (63%) of an amideof type C (see Scheme 1).

MS (ES+), m/z=387

Step 8:

According to M12, 0.43 g (1.11 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 1.26 g of tin chloride to give 0.163 g (43%) ofthe expected product D (see Scheme 1).

MS (ES+), m/z=339

¹H NMR (DMSO, 400 MHz), 8.3 ppm (1H, t); 7.9 ppm (2H, m); 7.3 ppm (2H,m); 4.4 ppm (2H, t); 4.0 ppm (2H, d); 2.4 ppm (3H, s); 1.8 ppm (2H, t);1.4 ppm (9H, s); 0.85 ppm (3H, t)

Example 504-(3-tert-Butyl-8-oxo-1-propyl-1,6,7,8-tetrahydro-1H-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile

(R1=tert-butyl; R2=propyl; R3=4-cyanophenyl)

Step 7:

According to M9, 0.449 g (1.76 mmol) of5-tert-butyl-4-nitro-2-propyl-2H-pyrazole-3-carboxylic acid (A) isreacted with 0.346 g (1.76 mmol) of 4-(2-aminoethanoyl)benzonitrilehydrochloride (Yakagaku Zasshi, 72, 305-307, 1952) to give 0.36 g (51%)of an amide of type C (see Scheme 1).

MS (ES−), m/z=396

Step 8:

According to M12, 0.36 g (0.9 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 1.02 g of tin chloride to give 0.116 g (37%) ofthe expected product D (see Scheme 1).

MS (ES+), m/z=350

¹H NMR (DMSO, 400 MHz), 8.35 ppm (1H, t); 8.2 ppm (2H, m); 8.0 ppm (2H,m); 4.4 ppm (2H, t); 4.0 ppm (2H, d); 1.8 ppm (2H, m); 1.4 ppm (9H, s);0.85 ppm (3H, t)

Example 513-tert-Butyl-5-(2,4-dimethoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=tert-butyl; R2=propyl; R3=2,4-dimethoxyphenyl)

Step 7:

According to M9, 0.449 g (1.76 mmol) of5-tert-butyl-4-nitro-2-propyl-2H-pyrazole-3-carboxylic acid (A) isreacted with 0.407 g (1.76 mmol) of2-amino-1-(2,4-dimethoxyphenyl)ethanone (J. Chem. Res. Miniprint, 7,1581-1597, 1989) to give 0.59 g (77%) of an amide of type C (see Scheme1).

MS (ES+), m/z=433

Step 8:

According to M12, 0.59 g (1.36 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 1.54 g of tin chloride dihydrate to give 0.184g (35%) of the expected product D (see scheme 1).

MS (ES+), m/z=385

¹H NMR (DMSO, 400 MHz), 8.4 ppm (1H, t); 7.55 ppm (1H, m); 6.6 ppm (2H,m); 4.35 ppm (2H, q); 3.9 ppm (3H, s); 3.8 ppm (5H, m); 1.8 ppm (2H, m);1.35 ppm (9H, s); 0.8 ppm (3H, t)

Example 523-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione

(R1=butyl; R2=ethyl; R3=phenyl)

Step 9:

0.65 g (2 mmol) of3-butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-oneis reacted with 1.77 g (4 mmol) of Lawesson's reagent and refluxed intoluene overnight to give 0.4 g (60%) of the desired thiolactam of typeE (see Scheme 1).

Rf (95/5 CH₂Cl₂/acetone)=0.65

m.p.: 151.5° C.

MS (ES+), m/z=327

¹H NMR (CDCl₃, 400 MHz), 8.8 ppm (1H, t); 8.0 ppm (2H, m); 7.4 ppm (3H,m); 4.8 ppm (2H, q); 4.2 ppm (2H, d); 2.8 ppm (2H, m); 1.7 ppm (2H, m);1.5 ppm (3H, m); 1.4 ppm (2H, m); 0.9 ppm (3H, t)

Example 531-Ethyl-3-methyl-5-pyrid-3-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=3-pyridyl)

Step 7:

According to M8, 1.9 g (9.5 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) are reactedwith 2 g (9.5 mmol) of 2-amino-1-pyrid-3-ylethanone hydrochloride (Chem.Pharm. Bull., 32, 7, 2536-2543, 1984; J. Amer. Chem. Soc., 67,1468-1472, 1945) to give 2.2 g (73%) of an amide of type C (see Scheme1).

Rf (90/10 CH₂Cl₂/acetone)=0.27

¹H NMR (CDCl₃, 400 MHz), 9.55 ppm (1H, t); 9.2 ppm (1H, s); 8.8 ppm (1H,d); 7.95 ppm (2H, m); 5.0 ppm (2H, d); 4.2 ppm (2H, q); 2.4 ppm (3H, s);1.4 ppm (3H, t)

Step 8:

According to M12, 1.1 g (3.47 mmol) of the amide C (see scheme 1) arerefluxed in ethanol with 3.9 g (5 eq.) of tin chloride dihydrate to give0.26 g (28%) of the expected product D (see scheme 1).

m.p.=178° C.

MS (ES+), m/z=270

¹H NMR (DMSO, 400 MHz), 9.2 ppm (1H, s); 8.7 ppm (1H, d); 8.4 ppm (1H,d); 8.3 ppm (1H, t); 7.5 ppm (1H, dd); 4.4 ppm (2H, q); 4.1 ppm (2H, d);2.3 ppm (3H, s); 1.4 ppm (3H, t)

Example 541-Ethyl-3-methyl-5-pyrid-2-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=2-pyridyl)

Step 7:

According to M8, 1.9 g (9.5 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) are reactedwith 2 g (9.5 mmol) of 2-amino-1-pyrid-2-ylethanone hydrochloride (J.Amer. Chem. Soc., 67, 1468-1472, 1945; J. Chem. Soc., 753, 1938) to give2.2 g (73%) of an amide of type C (see Scheme 1).

Rf (90/10 CH₂Cl₂/acetone)=0.38

MS (ES+), m/z=318

¹H NMR (CDCl₃, 400 MHz), 9.5 ppm (1H, bs); 8.8 ppm (1H, m); 8.0 ppm (2H,m); 7.7 ppm (1H, m); 5.0 ppm (2H, d); 4.2 ppm (2H, q); 2.4 ppm (3H, s);1.4 ppm (3H, t)

Step 8:

According to M12, 1.1 g (3.47 mmol) of the amide C (see scheme 1) arerefluxed in ethanol with 3.9 g (5 eq.) of tin chloride dihydrate to give0.19 g (20%) of the expected product D (see Scheme 1).

m.p.=153° C.

MS (ES+), m/z=270

¹H NMR (DMSO, 400 MHz), 8.7 ppm (H, d); 8.3 ppm (21H, m); 8.0 ppm (1H,t); 7.5 ppm (1H, dd); 4.5 ppm (2H, q); 4.4 ppm (2H, d); 2.3 (3H, s); 1.4ppm (3H, t)

Example 551-Ethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide

(R1=methyl; R2=ethyl; R3=phenyl)

Step 10:

According to M13, 2 g (7 mmol) of1-ethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thioneare reacted with 0.21 g of 80% sodium hydride in refluxing THF for 1 h,followed by addition of 0.52 ml of methyl iodide, at room temperature.The mixture is refluxed for 2 h to give 2.1 g (100%) of the expectedmethylsulphanyl G (see scheme 1).

MS (ES+), m/z=299

¹H NMR (CDCl₃, 400 MHz), 8.1 ppm (2H, d); 7.5 ppm (3H, m); 4.5 ppm (4H,m); 2.5 ppm (3H, s); 2.4 ppm (3H, s); 1.5 ppm (3H, t)

Step 11: 0.5 g (1.67 mmol) of the methylsulphanyl G is reacted with 0.14g (2 eq.) of cyanamide to give 0.29 g (60%) of the desired product F(see scheme 1).

Rf (95/5 CH₂Cl₂/MeOH)=0.32

m.p.=280° C.

MS (ES+), m/z=293

¹H NMR (DMSO, 400 MHz), 9.5 ppm (1H, s); 8.2 ppm (2H, m); 7.5 ppm (3H,m); 4.5 ppm (2H, q); 4.2 ppm (2H, s); 2.3 ppm (3H, s); 1.4 ppm (3H, t)

Example 56N-[4-(1-Ethyl-3-methyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)phenyl]-(phenylsulphonyl)benzenesulphonamide,

(R1=methyl; R2=ethyl; R3=4-N-(phenylsulphonyl)benzenesulphonamidephenyl)

0.2 g (0.7 mmol) of5-(4-aminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,is introduced into a round-bottomed flask and 10 ml of acetonitrile areadded, followed by 0.158 g (1.41 mmol) of 1,4-diazabicyclo[2.2.2]octane,and 0.116 ml (0.91 mmol) of benzenesulphonyl chloride. The reactionmixture is stirred overnight at room temperature and then evaporated todryness to give 0.54 g of an oily compound. The crude product ispurified by flash chromatography using the following elution gradient:from CH₂Cl₂ to 98/2 CH₂Cl₂/methanol. After evaporation andcrystallization from methanol, 0.19 g (48%) of a yellow powder areobtained.

MS (ES+), m/z=564

m.p.=>230° C.

¹H NMR (CDCl₃, 400 MHz), 1.5 ppm (3H, t); 2.4 ppm (3H, s); 4.1 ppm (2H,m); 4.55 ppm (2H, q); 6.25 ppm (1H, m); 7.1 ppm (2H, m); 7.6 ppm (4H,m); 7.7 ppm (2H, m); 7.85 ppm (6H, m)

Example 573-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidene-cyanamide

(R1=tert-butyl; R2=ethyl; R3=phenyl)

Step 10:

According to M13, 1.65 g (5.05 mmol)3-tert-butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thioneare reacted with 0.15 g of 80% sodium hydride in refluxing THF for 1hour, followed by addition of 0.38 ml of methyl iodide, at roomtemperature. The mixture is refluxed for 2 h to give 1.55 g (90%) of theexpected methylsulphanyl G (see scheme 1).

Step 11:

0.5 g (1.47 mmol) of the methylsulphanyl G is reacted with 0.12 g (2eq.) of cyanamide to give 0.185 g (38%) of the expected product of typeF (see Scheme 1).

Rf (95/5 CH₂Cl₂/methanol)=0.57

m.p.=250° C.

MS (ES+), m/z=335

¹H NMR (DMSO, 400 MHz), 9.5 ppm (1H, s); 8.1 ppm (2H, d); 7.5 ppm (3H,d); 4.5 ppm (2H, q); 4.2 ppm (2H, bs); 1.4 ppm (6H, s); 1.35 ppm (3H, m)

Example 581-Cyclopropylmethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,

(R1=methyl; R2=cyclopropylmethyl; R3=phenyl)

Step 5:

According to M5, 1.9 g (9.5 mmol) ofethyl-3-methyl-4-nitro-1H-5-pyrazolecarboxylate (commercial) are reactedwith 5 g (37 mmol) of (bromomethyl)cyclopropane (commercial) in thepresence of 1.43 g (9.5 mmol) of sodium iodide to give 1.14 g (48%) of apyrazole A5 (see scheme 1).

Rf (80/20 cyclohexane/EtOAc)=0.47

¹H NMR (CDCl₃, 400 MHz), 4.45 ppm (2H, q); 4.05 ppm (2H, d); 2.5 ppm(3H, s); 1.4 ppm (3H, t); 1.3 ppm (1H, m); 0.6 ppm (2H, m); 0.4 ppm (2H,m)

Step 6:

1.14 g (4.5 mmol) of the pyrazole A5 (see scheme 1) are reacted with0.27 g (6.75 mmol) of sodium hydroxide in a mixture of methanol andwater to give 0.93 g (91%) of a pyrazole of type A (see Scheme 1).

MS (ES−), m/z=224

Step 7:

According to M9, 0.5 g (2.22 mmol) of2-(cyclopropylmethyl)-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid isreacted with 0.38 g (2.22 mmol) of 2-aminoacetophenone hydrochloride togive 1 g of the compound C (see Scheme 1).

MS (ES+), m/z=343

Step 8:

According to M12, 1 g (2.9 mmol) of compound C (see scheme 1) isrefluxed in ethanol with 2.5 g (11 mmol), of tin chloride dihydrate togive 0.17 g (27%) of the expected product D (see scheme 1).

Rf (90/10 CH₂Cl₂/acetone)=0.42

MS (ES+), m/z=295

¹H NMR (CDCl₃, 400 MHz), 7.95 ppm (2H, m); 7.5 ppm (3H, m); 6.15 ppm(1H, t); 4.4 ppm (2H, d); 4.1 ppm (2H, d); 2.45 ppm (3H, s); 1.45 ppm(1H, m); 0.5 ppm (2H, m); 0.45 ppm (2H, m)

Example 591-Allyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=allyl; R3=phenyl)

Step 5:

According to M5, 2.5 g (12.5 mmol) ofethyl-3-methyl-4-nitro-1H-5-pyrazolecarboxylate (commercial) are reactedwith 1.09 ml (12.5 mmol) of allyl bromide (commercial) in the presenceof 0.38 g (12.5 mmol) of 80% sodium hydride in 1,2-dimethoxyethane togive 0.35 g (12%) of a pyrazole A5 (see Scheme 1).

Rf (70/30 cyclohexane/EtOAc)=0.53

¹H NMR (CDCl₃, 400 MHz), 5.9-6 ppm (1H, m); 5.3 ppm (1H, d); 5.2 ppm(1H, d); 4.8 ppm (2H, d); 4.45 ppm (2H, q); 2.5 ppm (3H, s); 1.4 ppm(3H, t)

Step 6:

0.35 g (1.46 mmol) of the pyrazole A5 (see scheme 1) is reacted with0.09 g (2.25 mmol) of sodium hydroxide in a mixture of methanol andwater, to give 0.071 g (23%) of a pyrazole of type A (see Scheme 1).

MS (ES⁻), m/z=210

Step 7:

According to M9, 0.071 g (0.34 mmol) of2-allyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid is reacted with0.058 g (0.34 mmol) of 2-aminoacetophenone hydrochloride to give 0.174 gof compound C (see Scheme 1).

Step 8:

According to M12, 0.174 g (0.5 mmol) of compound C (see scheme 1) isrefluxed in ethanol with 0.38 g (1.68 mmol) of tin chloride dihydrate togive 0.01 g (11%) of the expected product D (see Scheme 1).

Rf (90/10 CH₂Cl₂/acetone)=0.30

MS (ES+), m/z=281

Example 601-Ethyl-3-methyl-5-(4-trifluoromethylphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=4-trifluoromethylphenyl)

Step 7:

According to M9, 0.33 g (1.67 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) is reactedwith 0.4 g (1.67 mmol) of 2-amino-1-(4-trifluoromethylphenyl)ethanonehydrochloride (J. Amer. Chem. Soc., 75, 5884-5886, 1953; J. Org. Chem.,42, 5, 868-871, 1977) to give a crude amide of type C (see scheme 1).

MS (ES−), m/z=383

Step 8:

According to M12, 0.64 g (1.67 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 1.9 g (5 eq.) of tin chloride dihydrate to give0.153 g (27%) of the expected product of type D (see Scheme 1).

Rf (90/10 CH₂Cl₂/acetone)=0.22

m.p.=195° C.

MS (ES+), m/z=337

¹H NMR (DMSO, 400 MHz), 8.4 ppm (1H, t); 8.3 ppm (2H, d); 8.0 ppm (2H,d); 4.5 ppm (2H, q); 4.1 ppm (2H, d); 2.4 ppm (3H, s); 1.4 ppm (3H, t)

Example 611-Ethyl-3-isopropyl-5-(4-trifluoromethylphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=isopropyl; R2=ethyl; R3=4-trifluoromethylphenyl)

Step 7:

According to M9, 0.38 g (1.67 mmol) of2-ethyl-5-isopropyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) is reactedwith 0.4 g (1.67 mmol) of 2-amino-1-(4-trifluoromethylphenyl)ethanonehydrochloride (J. Amer. Chem. Soc., 75, 5884-5886, 1953; J. Org. Chem.,42, 5, 868-871, 1977) to give a crude amide of type C (see Scheme 1).

MS (ES−), m/z=411

Step 8:

According to M12, 0.69 g (1.67 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 1.9 g (5 eq.) of tin chloride dihydrate to give0.161 g (26.5%) of the expected product D (see Scheme 1).

Rf (90/10 CH₂Cl₂/acetone)=0.28

m.p.=133

MS (ES+), m/z=364

¹H NMR (DMSO, 400 MHz), 8.3 ppm (1H, t); 8.2 ppm (2H, d); 7.9 ppm (2H,d); 4.4 ppm (2H, q); 4.0 ppm (2H, d); 3.3 ppm (1H, m); 1.4 to 1.3 ppm(9H, m)

Example 621-Ethyl-3-methyl-5-(4-trifluoromethylphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=tert-butyl; R2=ethyl; R3=4-trifluoromethylphenyl)

Step 7:

According to M9, 0.4 g (1.67 mmol) of5-tert-butyl-2-ethyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) isreacted with 0.4 g (1.67 mmol) of2-amino-1-(4-trifluoromethylphenyl)ethanone hydrochloride (J. Amer.Chem. Soc., 75, 5884-5886, 1953; J. Org. Chem., 42, 5, 868-871, 1977) togive a crude amide of type C (see Scheme 1).

MS (ES−), m/z=425

Step 8:

According to M12, 0.712 g (1.67 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 1.9 g (5 eq.) of tin chloride dihydrate to give0.14 g (22%) of the expected product D (see Scheme 1).

Rf (90/10 CH₂Cl₂/acetone)=0.33

m.p.=144° C.

MS (ES+), m/z=379

¹H NMR (DMSO, 400 MHz), 8.3 ppm (1H, t); 8.2 ppm (2H, d); 7.9 ppm (2H,d); 4.4 ppm (2H, q); 4.1 ppm (2H, d); 1.4 ppm (9H, s); 1.35 ppm (3H, t)

Example 633-Isopropyl-1-propyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione

(R1=isopropyl; R2=propyl; R3=p-tolyl)

Step 9:

0.9 g (2.7 mmol) of3-isopropyl-1-propyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-oneis reacted with 2.24 g (5.53 mmol) of Lawesson's reagent and refluxed intoluene overnight to give 0.73 g (77%) of the thiolactam of type E (seescheme 1).

Rf (CH₂Cl₂)=0.22

m.p.=162.9° C.

MS (ES+), m/z=340.9

¹H NMR (CDCl₃, 400 MHz) 0.9 ppm (3H, t); 1.35 ppm (6H, m); 1.9 ppm (2H,m); 2.4 ppm (3H, s); 3.3 ppm (1H, m); 4.15 ppm (2H, m); 4.75 ppm (2H,m); 7.2 ppm (2H, d); 7.9 ppm (2H, d); 8.65 ppm (1H, m)

Example 643,5-Di-tert-butyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione

(R1=tert-butyl; R2=propyl; R3=tert-butyl)

Step 9:

1.5 g (4.9 mmol) of3,5-di-tert-butyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-oneare reacted with 4 g (9.8 mmol) of Lawesson's reagent and refluxed intoluene overnight to give 1.4 g (90%) of the thiolactam of type E (seeScheme 1).

Rf (80/20 cyclohexane/EtOAc)=0.54

m.p.: 205° C.

MS (ES+), m/z=321

¹H NMR (CDCl₃, 400 MHz), 9.0 ppm (1H, m); 4.7 ppm (2H, m); 1.9 ppm (2H,m); 1.4 ppm (9H, s); 1.25 ppm (9H, s); 0.9 ppm (3H, t)

Example 655-tert-Butyl-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione

(R1=isopropyl; R2=propyl; R3=tert-butyl)

Step 9:

0.35 g (1.2 mmol) of5-tert-butyl-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-oneis reacted with 0.98 g (2.4 mmol) of Lawesson's reagent and refluxed intoluene overnight to give 0.25 g (68%) of the thiolactam of type E (seeScheme 1).

Rf (70/30 cyclohexane/EtOAc)=0.67

m.p.: 165° C.

MS (ES+), m/z=307

¹H NMR (CDCl₃, 400 MHz), 8.8 ppm (1H, m); 4.7 ppm (2H, m); 3.75 ppm (2H,m); 3.2 ppm (1H, m); 1.9 ppm (2H, m); 1.3 ppm (6H, d); 1.25 ppm (9H, s);0.9 ppm (3H,t)

Example 661-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione

(R1=isopropyl; R2=ethyl; R3=p-tolyl)

Step 9:

0.62 g (2 mmol) of1-ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-oneis reacted with 1.62 g (4 mmol) of Lawesson's reagent and refluxed intoluene overnight to give 0.567 g (87%) of the desired thiolactam oftype E (see Scheme 1).

Rf (98/2 CH₂Cl₂/MeOH)=0.46

m.p.: 178° C.

MS (ES+), m/z=327

¹H NMR (CDCl₃, 400 MHz), 8.5 ppm (1H, bs); 7.8 ppm (2H, d); 7.15 ppm(2H, d); 4.75 ppm (2H, q); 4.1 ppm (2H, bs); 3.2 ppm (1H, m); 2.3 ppm(3H, s); 1.4 ppm (3H, t); 1.3 ppm (6H, d)

Example 675-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione

(R1=isopropyl; R2=ethyl; R3=tert-butyl)

Step 9:

0.4 g (1.45 mmol) of5-tert-butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-oneis reacted with 1.17 g (2.9 mmol) of Lawesson's reagent and refluxed intoluene overnight to give 0.193 g (46%) of the desired thiolactam oftype E (see Scheme 1).

Rf (98/2 CH₂Cl₂/MeOH)=0.43

m.p.: 218° C.

MS (ES+), m/z=293

¹H NMR (DMSO, 400 MHz), 10.35 ppm (1H, bs); 4.65 ppm (2H, q); 3.9-3.3ppm (2H, bs); 3.1 ppm (1H, m); 1.3 ppm (3H, t); 1.2 ppm (6H, d); 1.15ppm (9H, s)

Example 68(±)3-sec-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=sec-butyl; R2=ethyl; R3=phenyl)

Synthesis of the Pyrazole (Following Steps 1, 2, 3, 5 and 6):

Step 1:

3.44 g (149.8 mmol) of sodium are dissolved portionwise in 200 ml ofanhydrous ethanol under nitrogen, at room temperature. 20.35 ml (149.8mmol) of diethyl oxalate in 60 ml of anhydrous ethanol are added. 15 g(149.8 mmol) of 3-methyl-2-pentanone are added. The reaction mixture isrefluxed for 3 h, under nitrogen and with stirring, and is thenevaporated to dryness; the residue is taken up in 300 ml; of HCl (1.2N)and then extracted with diethyl ether (3 times 200 ml). The organicphase is dried over sodium sulphate and then concentrated to give 26.1 g(89%) of a colourless oil (compound A1, see scheme 1).

Rf (60/40 CH₂Cl₂/heptane)=0.4

¹H NMR (CDCl₃, 400 MHz), 0.9 ppm (3H, t); 1.1 ppm (3H, d); 1.4 ppm (3H1,t); 1.5 ppm (1H, m); 1.7 ppm (1H, m); 2.4 ppm (2H, m); 4.3 ppm (2H, q);6.4 ppm (1H, s); 14.6 ppm (1H, m).

Step 2:

8.25 g (125 mmol) of potassium hydroxide are dissolved in 120 ml ofwater and the reaction medium is cooled to 0° C. 25 g (125 mmol) ofcompound A1 (see scheme 1) are added portionwise and the mixture isstirred for 15 min at 0° C. 16.3 g (130.11 mmol) of hydrazine sulphateare added and the mixture is then stirred for 20 min at 0° C. It isstirred at room temperature overnight, after which 200 ml of water areadded and the mixture is extracted with dichloromethane (3×200 ml). Theorganic phase obtained is washed with saturated NaCl solution (1×200 ml)and then dried over sodium sulphate and concentrated. 24.5 g of anpowder are obtained.

The product is purified by flash chromatography (95/5 CH₂Cl₂/acetone) togive 17.6 g (68%) of a white powder (compound A6, see scheme 1).

Rf (95/5 CH₂Cl₂/acetone)=0.3

¹H NMR (CDCl₃, 400 MHz), 0.85 ppm (3H, t); 1.3 ppm (3H, d); 1.35 ppm(3H, t); 1.6 ppm (1H, m); 2.8 ppm (1H, m); 4.4 ppm (2H, m); 6.6 ppm (1H,s); 11.6 ppm (1H, m).

Step 3:

According to M3, 20.7 g (89.95 mmol) of copper(II) nitratehemipentahydrate (2.5 H₂O) and 100 ml of trifluoroacetic anhydride areintroduced into a round-bottomed flask, the mixture is stirred undernitrogen for 5 min and 17 g of compound A6 (see scheme 1) (80.87 mmol)dissolved in 100 ml of chloroform are then added. This mixture isrefluxed with stirring and under nitrogen for 5 hours. This product ispurified by flash chromatography (98/2 CH₂Cl₂/acetone) to give 20 g of ablueish oil. This product is taken up in 200 ml of HCl (10%) and thenextracted with diethyl ether (3 times 300 ml), and the organic phase isdried and concentrated to give 16.81 g (70%) of a colourless oil(compound A7, see scheme 1).

MS (ES−), m/z=239.91

Rf (97/3 CH₂Cl₂/acetone)=0.3

¹H NMR (CDCl₃, 400 MHz), 0.9 ppm (3H, t); 1.4 ppm (6H, m); 1.7 ppm (2H,m); 3.4 ppm (1H, m); 4.4 ppm (2H, q); 11.6 ppm (1H, m).

Step 5:

According to M4, 0.92 g (3.81 mmol) of compound A7 (see scheme 1) and0.5 ml (3.81 mmol) of diethyl sulphate are introduced into around-bottomed flask and the mixture is then refluxed with stirring andunder nitrogen for 1 h 30 min. After cooling to room temperature, 6 g ofice and 15 ml of HCl (10%) are added and the mixture is stirred and thenextracted with dichloromethane (3 times 40 ml). The organic phase isdried and concentrated to give 1.1 g of a colourless oil. This productis purified by flash chromatography (gradient: 9/1 to 7/3cyclohexane/ethyl acetate) to give 0.8 g (78%) of a white powder(compound A5, see scheme 1).

Rf (80/20 cyclohexane/ethyl acetate)=0.3

¹H NMR (CDCl₃, 400 MHz), 0.9 ppm (3H, t); 1.35 ppm (3H, m); 1.45 ppm(6H, m); 1.6 ppm (1H, m); 1.8 ppm (1H, m); 3.3 ppm (1H, m); 4.25 ppm(2H, q); 4.5 ppm (2H, q).

Step 6:

8.3 g (33.80 mmol) of compound A5 (see scheme 1) are dissolved in 40 mlof methanol, followed by addition of a solution of 2 g (50.7 mmol) ofsodium hydroxide in 40 ml of water. The mixture is stirred at RT for 2h. After evaporating off the methanol, the residue is taken up inCH₂Cl₂, an identical volume of water is added, followed by addition ofconcentrated (36%) hydrochloric acid to acidic pH, with stirring. Theorganic phase is dried over Na₂SO₄ and concentrated to give 7.5 g (98%)of a white powder (compound A, see scheme 1).

¹H NMR (CDCl₃, 400 MHz), 0.9 ppm (3H, m); 1.3 ppm (3H, m); 1.5 ppm (3H,m); 1.6 ppm (1H, m); 1.8 ppm (1H, m); 3.3 ppm (1H, m); 4.5 ppm (2H, q);9.3 ppm (1H, m).

Step 7:

According to M9, 0.434 g (1.8 mmol) of5-sec-butyl-2-ethyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) is reactedwith 0.309 g (1.8 mmol) of 2-aminoacetophenone hydrochloride to give acrude amide of type C (see Scheme 1).

MS (ES+), m/z=359

Step 8:

According to M12, 0.65 g (1.8 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 3.25 g (5 eq.) of tin chloride dihydrate togive 0.14 g (25%) of the expected product D (see scheme 1).

MS (ES+), m/z=311

¹H NMR (CDCl₃, 400 MHz), 7.9 ppm (2H, m); 7.4 ppm (3H, m); 7.2 ppm (1H,m); 4.5 ppm (2H, q); 4.1 ppm (2H, t); 3.1 ppm (1H, m); 1.8 ppm (1H, m);1.7 ppm (1H, m); 1.4 ppm (3H, t); 1.3 ppm (3H, d); 0.8 ppm (3H, t)

Example 69(±)3-sec-Butyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=sec-butyl; R2=ethyl; R3=4-pyridyl)

Synthesis of the Pyrazole: See Steps 1, 2, 3, 5 and 6 of Example 68.

Step 7:

According to M9, 0.434 g (1.8 mmol) of5-sec-butyl-2-ethyl-4-nitro-2H-pyrazole-3-carboxylic acid is reactedwith 0.376 g (1.8 mmol) of 2-amino-1-pyrid-4-ylethanone hydrchloride (J.Med. Chem., 38, 17, 3342-3350, 1995; J. Amer. Chem. Soc., 67, 1468-1472,1945) to give a crude amide of type C (see scheme 1).

MS (ES+), m/z=359.8

Step 8:

According to M12, 0.65 g (1.8 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 3.25 g (5 eq.) of tin chloride dihdyrate togive 0.135 g (24%) of the expected product D (see scheme 1).

m.p.: 86-88.5° C.

MS (ES+), m/z=312

¹H NMR (CDCl₃, 400 MHz), 8.8 ppm (2H, d); 7.8 ppm (2H, d); 7.2 ppm (1H,m); 4.6 ppm (2H, q); 4.1 ppm (2H, d); 3.1 ppm (1H, m); 1.9 ppm (1H, m);1.7 ppm (1H, m); 1.5 ppm (3H, t); 1.4 ppm (3H, d); 0.9 ppm (3H, q)

Example 70(±)3-sec-Butyl-5-phenyl-1-propyl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-one

(R1=sec-butyl; R2=propyl; R3=phenyl)

Synthesis of the Pyrazole: See Steps 1, 2 and 3 of Example 68 and theFollowing Steps 5 and 6.

Step 5:

According to M5, 4.90 g (66.32 mmol) of Li₂CO₃ are added, under a streamof nitrogen, to a solution of 6.4 g (26.53 mmol) of compound A7 (seescheme 1) in 110 ml of anhydrous DMF, followed by addition of 6.5 ml(66.32 mmol) of iodopropane. The reaction medium is heated at 60° C. for24 h. It is cooled to room temperature and then poured into 100 ml ofHCl (1.2N), the exothermicity being controlled by an ice bath. Afterextracting with dichloromethane (3 times 100 ml), the organic phaseobtained is washed with saturated NaCl solution (100 ml), dried overNa₂SO₄ and evaporated to dryness to give 7 g of an oily compound. Theproduct is purified by flash chromatography (gradient: 70/30 to 60/40heptane/CH₂Cl₂) to give 5 g (66%) of a colourless oil which crystallizes(compound A5, see scheme 1).

Rf (50/50 heptane/CH₂Cl₂)=0.3

¹H NMR (CDCl₃, 400 MHz), 0.90 ppm (6H, m); 1.25 ppm (3H, m); 1.40 ppm(3H, m); 1.60 ppm (1H, m); 1.80 ppm (3H, m); 3.30. ppm (1H, m); 4.25 ppm(2H, q); 4.40 ppm (2H, q).

Step 6:

4.94 g (18.41 mmol) of compound A5 (see scheme 1) are dissolved in 21 mlof methanol, followed by addition of a solution of 1.1 g (27.61 mmol) ofsodium hydroxide in 21 ml of water. This mixture is stirred at RT for 2h. After evaporating off the methanol, the residue is taken up in CH₂Cl₂and an identical volume of water is added, followed by addition ofconcentrated (36%) hydrochloric acid to acidic pH, with stirring. Theorganic phase is dried over Na₂SO₄ and concentrated to give 4.5 g (96%)of a white powder (compound A, see scheme 1).

¹H NMR (CDCl₃, 400 MHz), 0.9 ppm (6H, m); 1.3 ppm (3H, d); 1.6 ppm (1H,m); 1.8 ppm (1H, m); 1.9 ppm (2H, m); 3.3 ppm (1H, m); 4.4 ppm (2H, q);7.6 ppm (1H, m).

Step 7:

According to M9, 0.46 g (1.8 mmol) of5-sec-butyl-4-nitro-2-propyl-2H-pyrazole-3-carboxylic acid (A) isreacted with 0.31 g (1.8 mmol) of 2-aminoacetophenone hydrochloride togive a crude amide of type C (see scheme 1).

MS (ES+), m/z=373

Step 8:

According to M12, 0.67 g (1.8 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 3.35 g (5 eq.) of tin chloride dihydrate togive 0.035 g (6%) of the expected product D (see scheme 1).

MS (ES+), m/z=325

¹H NMR (CDCl₃, 400 MHz), 7.9 ppm (2H, m); 7.5 ppm (3H, m); 6.7 ppm (1H,m); 4.5 ppm (2H, m); 4.1 ppm (2H, m); 3.1 ppm (1H, m); 2.0 ppm to 1.6ppm (4H, m); 1.4 ppm (3H, d); 0.9 ppm (6H, m).

Example 71(±)3-sec-Butyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=sec-butyl; R2=propyl; R3=4-pyridyl)

Synthesis of the Pyrazole: See Steps 1, 2, 3, 5, 6 of Example 70.

Step 7:

According to M9, 0.46 g (1.8 mmol) of5-sec-butyl-4-nitro-2-propyl-2H-pyrazole-3-carboxylic acid is reactedwith 0.376 g (1.8 mmol) of 2-amino-1-pyrid-4-ylethanone hydrochloride(J. Med. Chem., 38, 17, 3342-3350, 1995; J. Amer. Chem. Soc., 67,1468-1472, 1945) to give a crude amide of type C (see scheme 1).

MS (ES+), m/z=373.6

Step 8:

According to M12, 0.62 g (1.66 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 3.36 g (5 eq.) of tin chloride dihydrate togive 0.1 g (17.3%) of the expected product D (see scheme 1).

m.p.: 110° C.

MS (ES+), m/z=325.8

¹H NMR (CDCl₃, 400 MHz), 8.7 ppm (2H, d); 7.7 ppm (2H, d); 7.0 ppm (1H,t); 4.5 ppm (2H, q); 4.0 ppm (2H, d); 3.1 ppm (1H, m); 1.9 ppm (2H, m);1.8 ppm (1H, m); 1.7 ppm (1H, m); 1.3 ppm (3H, d); 0.9 ppm (3H, m); 0. 8ppm (3H, m).

Example 723-Cyclohexyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-one

(R1=cyclohexyl; R2=ethyl; R3=phenyl)

Synthesis of the Pyrazole: See the Following Steps 1, 2, 3, 5 and 6.

Step 1:

2.46 g (107 mmol) of sodium are dissolved portionwise in 250 ml ofanhydrous ethanol under nitrogen at room temperature. 14.52 ml (107mmol) of diethyl oxalate in 60 ml of anhydrous ethanol are added. 15 g(107 mmol) of acetylcyclohexane are added. The reaction mixture isrefluxed for 3 h, under nitrogen and with stirring, and then evaporatedto dryness, the residue is taken up in 300 ml of HCl (1.2 N) and is thenextracted with diethyl ether (3 times 200 ml). The organic phase isdried over sodium sulphate and then concentrated to give 23.2 g (96%) ofa colourless oil (compound A1, see scheme 1).

Rf (60/40 CH₂Cl₂/n-heptane)=0.1

¹H NMR (CDCl₃, 400 MHz), 1.3 ppm (8H, m); 1.8 ppm (5H, m); 2.35 ppm(1H,m); 4.3 ppm (2H, q); 6.4 ppm (1H, s); 14.6 ppm (1H, m).

Step 2:

7 g (104 mmol) of potassium hydroxide are dissolved in 110 ml of waterand the reaction medium is cooled to 0° C. 25 g (110 mmol) of compoundA1 (see scheme 1) are added portionwise and the mixture is stirred for15 min at 0° C. 13.5 g (104 mmol) of hydrazine sulphate are added andthe mixture is then stirred for 20 min at 0° C. The resulting mixture isstirred overnight, 200 ml of water are then added and this mixture isextracted with dichloromethane (3 times 200 ml). The organic phaseobtained is washed with saturated NaCl solution (1×200 ml) and thendried over sodium sulphate and concentrated. 23.4 g of a powder areobtained.

The product is purified by flash chromatography (gradient: 97/3 to 90/10CH₂Cl₂/acetone) to give 15 g (61%) of a white powder (compound A6, seescheme 1).

Rf (95/5 CH₂Cl₂/acetone)=0.3

¹H NMR (CDCl₃, 400 MHz), 1.35 ppm (8H, m); 1.7 ppm (3H, m); 1.95 ppm(2H, m); 2.7 ppm (1H, m); 4.3 ppm (2H, q); 6.6 ppm (1H, s); 11.8 ppm(1H, m).

Step 3:

According to M3, 12.77 g (54.93 mmol) of copper(II) nitratehemipentahydrate (2.5 H₂O) and 100 ml of trifluoroacetic anhydride areintroduced into a round-bottomed flask, the mixture is stirred undernitrogen for 5 min and 11.1 g of compound A6 (see scheme 1) (49.93 mmol)dissolved in 100 ml of chloroform are then added. This mixture isrefluxed, with stirring and under nitrogen, for 5 hours. Afterevaporation to dryness, 18.6 g of a blueish oil are obtained. Thisproduct is taken up in 200 ml of HCl (10%) and then extracted with ether(3 times 300 ml) and the organic phase is dried and concentrated to give16.1 g of a colourless oil. This product is purified by flashchromatography (98/2 CH₂Cl₂/acetone) to give 7.1 g (53%) of a whitepowder (compound A7, see scheme 1).

Rf (97/3 CH₂Cl₂/acetone)=0.3

¹H NMR (CDCl₃, 400 MHz), 1.40 ppm (8H, m); 1.8 ppm (3H, m); 2.0 ppm (2H,m); 3.3 ppm (1H, m); 4.4 ppm (2H, q); 8.85 ppm (1H, m).

Step 5:

According to M4, 1.02 g (3.81 mmol) of compound A7 (see scheme 1) and0.5 ml (3.81 mmol) of diethyl sulphate are introduced into around-bottomed flask and the mixture is then refluxed, with stirring andunder nitrogen, for 1 h 30 min. After cooling to room temperature, 6 gof ice and 15 ml of HCl (1.2N) are added and this mixture is stirred andthen extracted with dichloromethane (3 times 40 ml). The organic phaseis dried and concentrated to give 1.1 g of a colourless oil. The productis purified by flash chromatography (5/5 CH₂Cl₂/heptane) to give 0.53 g(53%) of a white powder (compound A5, see scheme 1).

Rf (9/1 cyclohexane/ethyl acetate)=0.3

¹H NMR (CDCl₃, 400 MHz), 1.4 ppm (11H, m); 1.8 ppm (3H, m); 1.95 ppm(2H, m); 3.1 ppm (1H, m); 4.25 ppm (2H, q); 4.5 ppm (2H, q).

Step 6:

5.07 g (17.16 mmol) of compound A5 (see scheme 1) are dissolved in 20 mlof methanol, followed by addition of a solution of 1.03 g (25.75 mmol)of sodium hydroxide in 20 ml of water. This mixture is stirred at RT for2 h. After evaporating off the methanol, the residue is taken up inCH₂Cl₂ and an identical volume of water is added, followed by additionof concentrated (36%) hydrochloric acid to acidic pH, with stirring. Theorganic phase is dried over Na₂SO₄ and concentrated to give 4.6 g (100%)of a white powder (compound A, see scheme 1).

¹H NMR (CDCl₃, 400 MHz), 1.1 ppm to 1.5 ppm (8H, m); 3.0 ppm (1H, m);4.5 ppm (2H, q); 8.4 ppm (1H, m)

Step 7:

According to M9, 0.48 g (1.8 mmol) of5-cyclohexy1-2-ethyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) isreacted with 0.31 g (1.8 mmol) of 2-aminoacetophenone hydrochloride togive a crude amide of type C (see scheme 1).

MS (ES+), m/z=384.9

Step 8:

According to M12, 0.69 g (1.8 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 3.46 g (5 eq.) of tin chloride dihydrate togive 0.103 g (17%) of the expected product D (see Scheme 1).

MS (ES+), m/z=337

¹H NMR (CDCl₃, 400 MHz), 8.0 ppm (2H, m); 7.4 ppm (3H, m); 7.1 ppm (1H,m); 4.5 ppm (2H, q); 4.1 ppm (2H, d); 3.0 ppm (1H, m); 2.0 ppm (2H, m);1.8 ppm (2H, m); 1.7 ppm (2H, m); 1.5 ppm to 1.2 ppm (7H, m).

Example 733-Cyclohexyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-one

(R1=cyclohexyl; R2=ethyl; R3=4-pyridyl)

Synthesis of the Pyrazole: See Steps 1, 2, 3, 5 and 6 of Example 72

Step 7:

According to M9, 0.48 g (1.8 mmol) of5-cyclohexylethyl-4-nitro-2H-pyrazole-3-carboxylic acid is reacted with0.376 g (1.8 mmol) of 2-amino-1-pyrid-4-ylethanone hydrochloride (J.Med. Chem., 38, 17, 3342-3350, 1995; J. Amer. Chem. Soc., 67, 1468-1472,1945) to give a crude amide of type C (see scheme 1).

MS (ES+), m/z=385.9

Step 8:

According to M12, 0.63 g (1.63 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 3.12 g (5 eq.) of tin chloride dihydrate togive 0.092 g (15%) of the expected product D (see Scheme 1).

m.p.: 126-127° C.

MS (ES+), m/z=338

¹H NMR (CDCl₃, 400 MHz), 8.6 ppm (2H, d); 7.7 ppm (2H, d); 7.4 ppm (1H,t); 4.5 ppm (2H, q); 4.0 ppm (2H, d); 2.9 ppm (1H, m); 1.9 ppm (2H, m);1.8 ppm (2H, m); 1.6 ppm (2H, m); 1.4 ppm (3H, m); 1.3 ppm (4H, m).

Example 743-Cyclohexyl-5-phenyl-1-propyl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-one

(R1=cyclohexyl; R2=propyl; R3=phenyl)

Synthesis of the Pyrazole: See Steps 1, 2 and 3 of Example 72 and theFollowing Steps 5 and 6.

Step 5:

According to M5, 2.07 g (28.06 mmol) of Li₂CO₃ are added, under a streamof nitrogen, to a solution of 3 g (11.22 mmol) of compound A7 (seescheme 1) in 60 ml of anhydrous DMF, followed by addition of 2.73 ml(28.06 mmol) of iodopropane. The reaction medium is heated at 60° C. for48 h. After cooling to room temperature, the mixture is poured into 100ml of HCl (1.2N) and the exothermicity is controlled by an ice bath.This mixture is extracted with dichloromethane (3 times 100 ml) and theorganic phase obtained is washed with saturated NaCl solution (100 ml),dried over Na₂SO₄ and concentrated to give 3.6 g of an oily compound.This product is purified by flash (gradient: 70/30 to 30/70heptane/CH₂Cl₂) to give 2.85 g (82%) of a colourless oil whichcrystallizes (compound A5, see scheme 1).

Rf (60/40 heptane/CH₂Cl₂)=0.3

¹H NMR (CDCl₃, 400 MHz), 0.9 ppm (3H, t); 1.45 ppm (6H, m); 1.5 ppm (2H,m); 2.85 ppm (7H, m); 3.1 ppm (1H, q); 4.1 ppm (2H, q); 4.4 ppm (2H, q)

Step 6:

2.85 g (9.21 mmol) of compound A5 (see scheme 1) are dissolved in 10 mlof methanol, followed by addition of a solution of 0.55 g (13.81 mmol)of sodium hydroxide in 10 ml of water. The mixture is stirred at RT for2 h. After evaporating off the methanol, the residue is taken up inCH₂Cl₂ and an identical volume of water is added, followed by additionof concentrated (36%) hydrochloric acid to acidic pH, with stirring. Theorganic phase is dried over Na₂SO₄ and concentrated to give 2.52 g (97%)of a white powder (compound A, see scheme 1).

¹H NMR (CDCl₃, 400 MHz), 0.9 ppm (3H, m); 1.2 ppm to 1.6 ppm (5H, m);1.7 ppm to 2.0 ppm (7H, m); 3.1 ppm (1H, m); 4.4 ppm (2H, q); 8.7 ppm(1H, m)

Step 7:

According to M9, 0.5 g (1.8 mmol) of5-cyclohexyl-4-nitro-2-propyl-2H-pyrazole-3-carboxylic acid is reactedwith 0.31 g (1.8 mmol) of 2-aminoacetophenone hydrochloride to give acrude amide of type C (see Scheme 1).

MS (ES+), m/z=399

Step 8:

According to M12, 0.72 g (1.8 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 3.59 g (5 eq.) of tin chloride dihydrate togive 0.172 g (27%) of the expected product D (see Scheme 1).

MS (ES+), m/z=351

¹H NMR (CDCl₃, 400 MHz ), 7.8 ppm (2H, m); 7.4 ppm (4H, m); 4.5 ppm (2H,q); 4.0 ppm (2H, d); 2.9 ppm (1H, m); 1.9 ppm to 1.7 ppm (10H, m); 1.3ppm (2H, m); 0.9 ppm (3H, t).

Example 75 3-Cyclohexyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-one

(R1=cyclohexyl; R2=propyl; R3=4-pyridyl)

Synthesis of the Pyrazole: See Steps 1, 2, 3, 5 and 6 of Example 74

Step 7:

According to M9, 0.5 g (1.8 mmol) of5-cyclohexyl-4-nitro-2-propyl-2H-pyrazole-3-carboxylic acid is reactedwith 0.376 g (1.8 mmol) of 2-amino-1-pyrid-4-ylethanone hydrochloride(J. Med. Chem., 38, 17, 3342-3350, 1995; J. Amer. Chem. Soc., 67,1468-1472, 1945) to give a crude amide of type C (see Scheme 1).

MS (ES+), m/z=400

Step 8:

According to M12, 0.65 g (1.63 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 3.24 g (5 eq.) of tin chloride dihydrate togive 0.055 g (8.6%) of the expected product D (see Scheme 1).

m.p.: 152-1530° C.

MS (ES+), m/z=352

¹H NMR (CDCl₃, 400 MHz), 8.7 ppm (2H, d); 7.7 ppm (2H, d); 6.9 ppm (1H,t); 4.4 ppm (2H, m); 4.5 ppm (2H, d); 2.9 ppm (1H, m); 1.9 ppm to 1.6ppm (1OH, m); 1.3 ppm (2H, m); 0.8 ppm (3H, t).

Example 763-Cyclohexylmethyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=cyclohexylmethyl; R2=ethyl; R3=4-pyridyl)

Synthesis of the Pyrazole: See the Following Steps 1, 2, 5, 3 and 6.

Step 1:

4.33 g (188.26 mmol) of sodium are dissolved portionwise in 200 ml ofanhydrous ethanol under nitrogen at room temperature. 25.6 ml (188.26mmol) of diethyl oxalate in 50 ml of anhydrous ethanol are added. 24 g(171.11 mmol) of acetonylcyclohexane are added. The reaction mixture isrefluxed for 3 h under nitrogen and with stirring, and is thenevaporated to dryness and the residue is taken up in 300 ml of HCl (1.2N) and then extracted with diethyl ether (3 times 200 ml). The organicphase is dried over sodium sulphate and then concentrated to give 42.6 g(92%) of a colourless oil (compound A1, see scheme 1).

Rf (99/1 CH₂Cl₂/acetone)=0.5

¹H NMR (CDCl₃, 400 MHz), 1.0 ppm (2H, m); 1.25 ppm (3H, m); 1.4 ppm (3H,m); 1.7 ppm (6H, m); 1.8 ppm (1H, m); 2.35 ppm (2H, d); 4.4 ppm (2H, q);6.3 ppm (1H, s); 14.6 ppm (1H, m).

Step 2:

12.9 g (195.4 mmol) of potassium hydroxide are dissolved in 250 ml ofwater and the reaction medium is cooled to 0° C. 42.6 g (177 mmol) ofcompound Al (see scheme 1) are added portionwise and the mixture isstirred for 30 min at 0° C. 25.37 g (195 mmol) of hydrazine sulphate areadded and the mixture is then stirred for 45 min at 0° C. The resultingmixture is stirred overnight at room temperature, 200 ml of water arethen added and this mixture is extracted with dichloromethane (3 times200 ml). The organic phase obtained is washed with saturated NaClsolution (1×200 ml) and then dried over sodium sulphate andconcentrated. 40 g of an powder are obtained.

The product is purified by flash chromatography (99/1 to 95/5CH₂Cl₂/acetone) to give 20.7 g (50%) of a white powder (compound A6, seescheme 1).

Rf (97/3 CH₂Cl₂/acetone)=0.3

¹H NMR (CDCl₃, 400 MHz), 0.9 ppm (2H, m); 1.2 ppm (4H, m); 1.4 ppm (3H,m); 1.65 ppm (6H, m); 2.6 ppm (H, d); 6.6 ppm (1H, s); 10.5 ppm (1H, m)

Step 5:

According to M4, 8.5 g (36 mmol) of compound A6 (see scheme 1) and 2.38ml (18 mmol) of diethyl sulphate are introduced into a round-bottomedflask and the mixture is then heated at 125-130° C., with stirring andunder nitrogen, for 4 h. After cooling to room temperature, 120 g of iceand 120 ml of HCl (1.2N) are added with stirring and the resultingmixture is then extracted with dichloromethane (3 times 250 ml). Theorganic phase is dried and concentrated to give 10.81 g of a brown oil.This product is purified by flash chromatography (9/1 cyclohexane/ethylacetate) to give 5.76 g (60%) of a white powder (compound A8, see scheme1).

Rf (80/20 cyclohexane/ethyl acetate)=0.3

¹H NMR (CDCl₃, 400 MHz), 0.9 ppm (2H, m); 1.2 ppm (4H, m); 1.4 ppm (5H,m); 1.60 ppm (6H, m); 2.5 ppm (2H, d); 4.35 ppm (2H, q); 4.5 ppm (2H,q); 6.6 ppm (1H, s)

Step 3:

According to M3, 20.7 g (89.95 mmol) of copper(II) nitratehemipentahydrate (2.5 H₂O) and 100 ml of trifluoroacetic anhydride areintroduced into a round-bottomed flask and the mixture is stirred undernitrogen for 5 min, followed by addition of 17 g of compound A8 (80.87mmol) dissolved in 100 ml of chloroform. This mixture is refluxed, withstirring and under nitrogen, for 5 hours. This product is purified byflash chromatography (98/2 CH₂Cl₂/acetone) to give 20 g of a blueishoil. This product is taken up in 200 ml of HCl (1.2N) and then extractedwith ether (3 times 300 ml) and the organic phase is dried andconcentrated to give 16.81 g (70%) of a colourless oil (compound A5, seescheme 1).

MS (ES+), m/z=309.90

Rf (70/30 heptane/CH₂Cl₂)=0.3

¹H NMR (CDCl₃, 400 MHz), 1.0 ppm (2H, m); 1.2 ppm (3H, m); 1.4 ppm (3H,m); 1.45 ppm (3H, m); 1.7 ppm (6H, m); 2.8 ppm (2H, d); 4.3 ppm (2H, q);4.5 ppm (2H, q)

Step 6:

8.3 g (33.80 mmol) of compound A5 (see scheme 1) are dissolved in 40 mlof methanol, followed by addition of a solution of 2 g (50.7 mmol) ofsodium hydroxide in 40 ml of water. This mixture is stirred at RT for 2h. After evaporating off the methanol, the residue is taken up in CH₂Cl₂and an identical volume of water is added, followed by addition ofconcentrated (36%) HCl to acidic pH, with stirring. The organic phase isdried over Na₂SO₄ and concentrated to give 7.5 g (98%) of a white powder(compound A, see scheme 1).

¹H NMR (CDCl₃, 400 MHz), 1.0 ppm (2H, m); 1.2 ppm (3H, m); 1.5 ppm (3H,t); 1.7 ppm (6H, m); 2.8 ppm (2H, d); 4.6 ppm (2H, q); 8.55 ppm (1H, m).

Step 7:

According to M9, 0.281 g (1.8 mmol) of5-cyclohexylmethyl-2-ethyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) isreacted with 0.376 g (1.8 mmol) of 2-amino-1-pyrid-4-ylethanonehydrochloride (J. Med. Chem., 38, 17, 3342-3350, 1995; J. Amer. Chem.Soc., 67, 1468-1472, 1945) to give a crude amide of type C (see Scheme1).

MS (ES+), m/z=400.01

Step 8:

According to M12, 0.61 g (1.53 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 3.02 g (5 eq.) of tin chloride dihydrate togive 0.073 g (12%) of the expected product D (see scheme 1).

MS (ES+), m/z=352.32

¹H NMR (CDCl₃, 400 MHz), 8.7 ppm (2H, d); 7.8 ppm (2H, d); 7.3 ppm (1H,t); 4.6 ppm (2H, q); 4.1 ppm (2H, d); 2.7 ppm (2H, d); 1.7 ppm (6H, m);1.5 ppm (3H, t); 1.3 ppm to 1.0 ppm (5H, m).

Example 773-Cyclohexylmethyl-5-phenyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=cyclohexylmethyl; R2=propyl; R3=phenyl)

Synthesis of the Pyrazole: See Steps 1 and 2 of Example 76 and theFollowing Steps 5, 3 and 6.

Step 5:

According to M5, 3.9 g (52.89 mmol) of Li₂CO₃ are added, under a streamof nitrogen, to a solution of 5 g (21.16 mmol) of compound A6 (seescheme 1) in 100 ml of anhydrous DMF, followed by addition of 5.2 ml(52.89 mmol) of iodopropane. The reaction medium is heated at 70° C. for48 h. After cooling to room temperature, the mixture is poured into 100ml of HCl (1.2N) and the exothermicity is controlled with an ice bath.This mixture is extracted with dichloromethane (3 times 200 ml) and theorganic phase obtained is washed with saturated NaCl solution (200 ml),dried over Na₂SO₄ and evaporated to dryness to give 5.8 g of a brownoil. This product is purified by flash chromatography (gradient: 50/50to 30/70 heptane/CH₂Cl₂) to give 1.15 g (20%) of a colourless oil whichcrystallizes (compound A8, see scheme 1).

Rf (60/40 heptane/CH₂Cl₂)=0.3

¹H NMR (CDCl₃, 400 MHz), 0.9 ppm (5H, m); 1.2 ppm (3H, m); 1.4 ppm (3H,m); 1.7 ppm (6H, m); 1.8 ppm (2H, m); 2.5 ppm (2H, d); 4.3 ppm (2H, q);4.5 ppm (2H, q); 6.6 ppm (1H, s)

Step 3:

According to M3, 0.96 g (4.13 mmol) of copper(II) nitratehemipentahydrate (2.5 H₂O) and 20 ml of trifluoroacetic anhydride areintroduced into a round-bottomed flask and the mixture is stirred undernitrogen for 5 min, followed by addition of 1.15 g of compound A8 (seescheme 1) (4.13 mmol) dissolved in 20 ml of chloroform. This mixture isrefluxed, with stirring and under nitrogen, for 3 hours. This product istaken up in 10 g of ice and 40 ml of HCl (10%) and then extracted withdichloromethane (3 times 100 ml) and the organic phase is dried andconcentrated to give 1.3 g of a colourless oil. The product is purifiedby flash chromatography (gradient: 70/30 to 50/50 heptane/CH₂Cl₂) togive 1.08 g (80%) of a white powder (compound A5, see scheme 1).

Rf (60/40 heptane/CH₂Cl₂)=0.3

¹H NMR (CDCl₃, 400 MHz), 0.9 ppm (3H, m); 1.0 ppm to 1.3 ppm (5H, m);1.4 ppm (3H, m); 1.7 ppm (6H, m); 1.9 ppm (2H, m); 2.7 ppm (2H, d); 4.1ppm (2H, t); 4.5 ppm (2H, q)

Step 6:

1 g (3.09 mmol) of compound A5 (see scheme 1) is dissolved in 5 ml ofmethanol, followed by addition of a solution of 0.185 g (4.64 mmol) ofsodium hydroxide in 5 ml of water. This mixture is stirred at RT for 2h. After evaporating off the methanol, the residue is taken up in CH₂Cl₂and an identical volume of water is added, followed by addition ofconcentrated (36%) hydrochloric acid to acidic pH, with stirring. Theorganic phase is dried over Na₂SO₄ and concentrated to dryness to give0.89 g (97%) of a white powder (compound A, see scheme 1).

¹H NMR (CDCl₃, 400 MHz), 0.9 ppm to 1.0 ppm (5H, m); 1.2 ppm (3H, m);1.4 ppm (3H, m); 1.6 ppm (6H, m); 1.9 ppm (2H, m); 2.7 ppm (2H, d); 4.1ppm (2H, t); 4.5 ppm (2H, q)

Step 7:

According to M9, 0.463 g (1.57 mmol) of5-cyclohexylmethyl-4-nitro-2-propyl-2H-pyrazole-3-carboxylic acid (A) isreacted with 0.269 g (1.57 mmol) of 2-aminoacetophenone hydrochloride togive a crude amide of type C (see scheme 1).

MS (ES+), m/z=413.04

Step 8:

According to M12, 0.65 g (1.57 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 3.24 g (5 eq.) of tin chloride dihydrate togive 0.092 g (14%) of the expected product D (see scheme 1).

MS (ES+), m/z=364.90

¹H NMR (CDCl₃, 400 MHz), 8.0 ppm (2H, m); 7.5 ppm (3H, m); 6.4 ppm (1H,s); 4.5 ppm (2H, m); 4.1 ppm (2H, d); 2.7 ppm (2H, d); 1.9 ppm (2H, m);1.7 ppm (6H, m); 1.3 ppm to 0.8 ppm (8H, m).

Example 783-Cyclohexylmethyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=cyclohexylmethyl; R2=propyl; R3=4-pyridyl)

Synthesis of the Pyrazole: See Steps 1, 2, 5, 3 and 6 of Example 77

Step 7:

According to M9, 0.464 g (1.57 mmol) of5-cyclohexylmethyl-4-nitro-2-propyl-2H-pyrazole-3-carboxylic acid (A) isreacted with 0.328 g (1.57 mmol) of 2-amino-1-pyrid-4-ylethanonehydrochloride (J. Med. Chem., 38, 17, 3342-3350, 1995; J. Amer. Chem.Soc., 67, 1468-1472, 1945) to give a crude amide of type C (see Scheme1).

MS (ES+), m/z=414.02

Step 8:

According to M12, 0.59 g (1.43 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 2.92 g (5 eq.) of tin chloride dihydrate togive 0.101 g (15.4%) of the expected product D (see Scheme 1).

MS (ES+), m/z=366.38

¹H NMR (CDCl₃, 400 MHz), 8.7 ppm (2H, d); 7.7 ppm (2H, d); 6.9 ppm (1H,m); 4.5 ppm (2H, m); 4.0 ppm (2H, d); 2.7 ppm (2H, d); 1.8 ppm (3H, m);1.7 ppm (5H, m); 1.0 ppm to 0.8 ppm (8H, m).

Example 793-Cyclohexylmethyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=cyclohexylmethyl; R2=ethyl; R3=phenyl)

Synthesis of the Pyrazole: See Steps 1, 2, 5, 3 and 6 of Example 76

Step 5:

According to M4, 8.5 g (36 mmol) of compound A6 (see scheme 1) and 2.38ml (18 mmol) of diethyl sulphate are introduced into a round-bottomedflask and the mixture is then heated at 125-130° C., with stirring andunder nitrogen, for 4 h. After cooling to room temperature, 120 g of iceand 120 ml of HCl (1.2N) are added and the resulting mixture is stirredand then extracted with dichloromethane (3 times 250 ml). The organicphase is dried and concentrated to give 10.81 g of a brown oil. Thisproduct is purified by flash chromatography (9/1 cyclohexane/ethylacetate) to give 5.76 g (60%) of a white powder (compound A8, see scheme1).

Rf (80/20 cyclohexane/ethyl acetate)=0.3

¹H NMR (CDCl₃, 400 MHz), 0.9 ppm (2H, m); 1.2 ppm (4H, m); 1.4 ppm (5H,m); 1.6 ppm (6H, m); 2.5 ppm (2H, d); 4.35 ppm (2H, q); 4.5 ppm (2H, q);6.6 ppm (1H, s)

Step 3:

According to M3, 20.7 g (89.95 mmol) of copper(II) nitratehemipentahydrate (2.5 H₂O) and 100 ml of trifluoroacetic anhydride areintroduced into a round-bottomed flask, this mixture is stirred undernitrogen for 5 min and 17 g of compound A8 (see scheme 1) (80.87 mmol)dissolved in 100 ml of chloroform are then added. This mixture isrefluxed, with stirring and under nitrogen, for 5 hours. This product ispurified by flash chromatography (98/2 CH₂Cl₂/acetone) to give 20 g of ablueish oil. This product is taken up in 200 ml of HCl (10%) and thenextracted with ether (3 times 300 ml) and the organic phase is dried andconcentrated to give 16.81 g (70%) of a colourless oil (compound A5, seescheme 1).

MS (ES+), m/z=309.90

Rf (70/30 heptane/CH₂Cl₂)=0.3

¹H NMR (CDCl₃, 400 MHz), 1.0 ppm (2H, m); 1.2 ppm (3H, m); 1.4 ppm (3H,m); 1.45 ppm (3H, m); 1.7 ppm (6H, m); 2.8 ppm (2H, d); 4.3 ppm (2H, q);4.5 ppm (2H, q)

Step 6:

8.3 g (33.80 mmol) of compound A5 (see scheme 1) are dissolved in 40 mlof methanol, followed by addition of a solution of 2 g (50.7 mmol) ofsodium hydroxide in 40 ml of water. This mixture is stirred at RT for 2h. After evaporating off the methanol, the residue is taken up in CH₂Cl₂and an identical volume of water is added, followed by addition ofconcentrated (36%) of hydrochloric acid to acidic pH, with stirring. Theorganic phase is dried over Na₂SO₄ and concentrated to dryness to give7.5 g (98%) of a white powder (compound A, see scheme 1).

¹H NMR (CDCl₃, 400 MHz), 1.0 ppm (2H, m); 1.2 ppm (3H, m); 1.5 ppm (3H,t); 1.7 ppm (6H, m); 2.8 ppm (2H, d); 4.6 ppm (2H, q); 8.55 ppm (1H, m)

Step 7:

According to M9, 0.281 g (1.8 mmol) of5-cyclohexylmethyl-2-ethyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) isreacted with 0.309 g (1.8 mmol) of 2-aminoacetophenone hydrochloride togive a crude amide of type C (see scheme 1).

MS (ES+), m/z=399.60

Step 8:

According to M12, 0.72 g (1.8 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 3.59 g (5 eq.) of tin chloride dihydrate togive 0.132 g (21%) of the expected product D (see scheme 1).

MS (ES+), m/z=350.9

¹H NMR (CDCl₃, 400 MHz), 7.9 ppm (2H, m); 7.4 ppm (3H, m); 7.1 ppm (1H,m); 4.5 ppm (2H, t); 4.0 ppm (2H, d); 2.6 ppm (2H, d); 1.9 ppm (3H, m);1.6 ppm (5H, m); 1.4 ppm (3H, m); 1.1 ppm (3H, m); 0.9 ppm (2H, m).

Example 805-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-ylidenecyanamide

(R1=isopropyl; R2=ethyl; R3=tert-butyl)

Step 10:

According to M13, 0.96 g (3.28 mmol) of5-tert-butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]-diazepin-8-thioneis reacted with 0.0984 g of 80% sodium hydride in refluxing THF for 1 h,followed by addition, at room temperature, of 0.245 ml of methyl iodide.The mixture is refluxed for 2 h to give 1.14 g of the expectedmethylsulphanyl G (see scheme 1).

Rf (95/5 CH₂C1₂/acetone)=0.85

MS (ES+), m/z=307

Step 11:

1 g (3.26 mmol) of the methylsulphanyl G (see scheme 1) is reacted with0.27 g (2 eq.) of cyanamide to give 0.825 g (84%) of the expectedproduct of type F (see Scheme l).

Rf (95/5 CH₂Cl₂/methanol)=0.56

m.p.=243° C.

MS (ES+), m/z=301

¹H NMR (CDCl₃, 400 MHz), 8.6 ppm (1H, bs); 4.5 ppm (2H, q); 3.7 ppm (2H,bs); 3.2 ppm (1H, m); 1.4 ppm (3H, t); 1.3 ppm (6H, d); 1.25 ppm (9H, s)

Example 811-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-ylidenecyanamide

(R1=isopropyl; R2=ethyl; R3=p-tolyl)

Step 10:

According to M13, 0.61 g (1.87 mmol) of1-ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]-diazepin-8-thioneis reacted with 0.056 g of 80% sodium hydride in refluxing THF for 1 h,followed by addition, at room temperature, of 0.14 ml of methyl iodide.The mixture is refluxed for 2 h to give 0.71 g of the expectedmethylsulphanyl G (see scheme 1).

Rf (95/5 CH₂Cl₂/acetone)=0.78

MS (ES+), m/z=341

Step 11:

0.64 g (1.87 mmol) of the methylsulphanyl G (see scheme 1) is reactedwith 0.16 g (2 eq.) of cyanamide to give 0.43 g (69%) of the expectedproduct of type F (see Scheme 1).

Rf (95/5 CH₂Cl₂/methanol)=0.48

m.p.=245° C.

MS (ES+), m/z=335

¹H NMR (CDCl₃, 400 MHz), 8.8 ppm (1H, bs); 8.0 ppm (2H, d); 7.3 ppm (2H,d); 4.6 ppm (2H, q); 4.15 ppm (2H, bs); 3.3 ppm. (1H, m); 2.4 ppm (3H,s); 1.5 ppm (3H, t); 1.4 ppm (6H, d)

Example 821-Ethyl-3-isopropyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=isopropyl; R2=ethyl; R3=4-methoxyphenyl)

Step 7:

According to M10, 3.18 g (14 mmol) of2-ethyl-5-isopropyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) arereacted with 2.82 g (14 mmol) of 2-amino-1-(4-methoxyphenyl)ethanonehydrochloride to give 4.7 g (90%) of an amide of type C (see Scheme 1).

MS (ES+), m/z=375

¹H NMR (CDCl₃, 400 MHz), 8.0 ppm (2H, d); 7.7 ppm (1H, t); 7.0 ppm (2H,d); 4.95 ppm (2H, d); 4.25 ppm (2H, q); 3.9 ppm (3H, s); 3.55 ppm (1H,m); 1.5 ppm (3H, t); 1.3 ppm (GH, d)

Step 8:

According to M12, 4.7 g (12.5 mmol) of the amide C (see scheme 1) arerefluxed in ethanol with 14.2 g of tin chloride dihydrate to give 2.84 g(70%) of the expected product D (see Scheme 1).

MS (ES+), m/z=327

Rf (95/5 CH₂Cl₂/MeOH)=0.22

m.p.=150° C.

¹H NMR (DMSO, 400 MHz), 8.25 ppm (1H, t); 8.0 ppm (2H, d); 7.05 ppm (2H,d); 4.45 ppm (2H, q); 4 ppm (2H, d); 3.85 ppm (3H, s); 3.2 ppm (1H, m);1.35 ppm (3H, t); 1.3 ppm (6H, d)

Example 83

Step 9:

1-Ethyl-S-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione

(R1=methyl; R2=ethyl; R3=4-methoxyphenyl) 2.2 g (7.4 mmol) of1-ethyl-5-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-oneare refluxed in toluene with 6 g (14.8 mmol) of Lawesson's reagent togive 2 g (87%) of an expected compound of type E (see Scheme 1).

Rf (95/5 CH₂Cl₂/methanol)=0.7

m.p.: 209° C.

MS (ES+), m/z=315

¹H NMR (CDCl₃, 400 MHz), 8.35 ppm (1H, bs); 7.95 ppm (2H, d); 6.95 ppm(2H, d); 4.8 ppm (2H, q); 4.15 ppm (2H, bs); 3.9 ppm (3H, s); 2.4 ppm(3H, s); 1.5 ppm (3H, t)

Example 841-Ethyl-3-methyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide

(R1=methyl; R2=ethyl; R3=4-methoxyphenyl)

Step 10:

According to M13, 1.75 g (5.6 mmol) of1-ethyl-5-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thioneare reacted with 0.23 g of 60% sodium hydride in refluxing THF for 1 h,followed by addition, at room temperature, of 0.42 ml of methyl iodide.The mixture is refluxed for 2 h to give 2 g (100%) of the expectedmethylsulphanyl G (see Scheme 1).

Rf (95/5 CH₂Cl₂/methanol)=0.86

MS (ES+), m/z=329

Step 11:

2g (6.1 mmol) of the methylsulphanyl G (see Scheme 1) are reacted with0.52 g (2 eq.) of cyanamide to give 1.33 g (68%) of the expected productof type F (see scheme 1).

Rf (95/5 CH₂Cl₂/methanol)=0.5

m.p.=265° C.

MS (ES+), m/z=323

¹H NMR (DMSO, 400 MHz), 9.45 ppm (1H, bs); 8.1 ppm (2H, d); 7.1 ppm (2H,d); 4.45 ppm (2H, q); 4.15 ppm (2H, bs); 3.85 ppm (3H, s); 2.3 ppm (3H,s); 1.35 ppm (3H, t)

Example 853-Isopropyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=isopropyl; R2=propyl; R3=4-methoxy-phenyle)

Step 7:

According to M10, 3.38 g (14 mmol) of5-isopropyl-4-nitro-2-propyl-2H-pyrazole-3-carboxylic acid (A) arereacted with 2.82 g (14 mmol) of 2-amino-1-(4-methoxyphenyl)ethanonehydrochloride to give 4.58 g (84%) of an amide of type C (see scheme 1).

MS (ES+), m/z=389

¹H NMR (CDCl₃, 400 MHz), 8.0 ppm (2H, d); 7.7 ppm (1H, t); 7.0 ppm (2H,d); 4.95 ppm (2H, d); 4.2 ppm (2H, q); 3.9 ppm (3H, s); 3.55 ppm (1H,m); 1.9 ppm (2H, m); 1.3 ppm (6H, d); 0.95 ppm (3H, t)

Step 8:

According to M12, 4.58 g (16 mmol) of the amide C (see scheme 1) arerefluxed in ethanol with 13.3 g of tin chloride dihydrate to give 2.92 g(73%) of the expected product D (see scheme 1).

MS (ES+), m/z=341

¹H NMR (DMSO, 400 MHz), 8.2 ppm (1H, t); 8.0 ppm (2H, d); 7.05 ppm (2H,d); 4.4 ppm (2H, q); 4.0 ppm (211, d); 3.85 ppm (3H, s); 3.2 ppm (1H,m); 1.8 ppm (2H, m); 1.3 ppm (6H, d); 0.85 ppm (3H, t)

Rf (90/10 CH₂Cl₂/acetone)=0.37

m.p.=142° C.

Example 863-tert-Butyl-1-ethyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=tert-butyl; R2=ethyl; R3=4-methoxyphenyl)

Step 7:

According to M10, 3.38 g (14 mmol) of5-tert-butyl-2-ethyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) arereacted with 2.82 g (14 mmol) of 2-amino-1-(4-methoxyphenyl)ethanonehydrochloride to give 4.92 g (90%) of an amide of type C (see scheme 1).

MS (ES+), m/z=389

¹H NMR (CDCl₃, 400 MHz), 8.0 ppm (2H, d); 7.4 ppm (1H, bs); 7.0 pm (2H,d); 4.9 ppm (2H, d); 4.2 ppm (2H, q); 3.9 ppm (3H, s); 1.5 ppm (3H, t);1.4 ppm (9H, s)

Step 8:

According to M12, 4.92 g (13 mmol) of the amide C (see scheme 1) arerefluxed in ethanol with 14.3 g of tin chloride hydrate to give 2.1 g(49%) of the expected product D (see scheme 1).

MS (ES+), m/z=341

Rf (90/10 CH₂Cl₂/acetone)=0.32

m.p.=180° C.

¹H NMR (DMSO, 400 MHz), 8.3 ppm (1H, t); 8.0 ppm (2H, d); 7.1 ppm (2H,d); 4.4 ppm (2H, q); 4.0 ppm (2H, d); 3.85 ppm (3H, s); 1.45 ppm (9H,s); 1.35 ppm (3H, t)

Example 873-tert-Butyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=tert-butyl; R2=propyl; R3=4-methoxyphenyl)

Step 7:

According to M10, 3.57 g (14 mmol) of5-tert-butyl-4-nitro-2-propyl-2H-pyrazole-3-carboxylic acid (A) arereacted with 2.82 g (14 mmol) of 2-amino-1-(4-methoxyphenyl)ethanonehydrochloride to give 5 g (89%) of an amide of type C (see scheme 1).

MS (ES+), m/z =403

¹H NMR (CDCl₃, 400 MHz), 8.0 ppm (2H, d); 7.4 ppm (1H, t); 6.95 ppm (2H,d); 4.9 ppm (2H, d); 4.1 ppm (2H, q); 3.9 ppm (3H, s); 1.9 ppm (2H, m);1.4 ppm (9H, s); 0.9 ppm (3H, t)

Step 8:

According to M12, 5 g (12 mmol) of the amide C (see scheme 1) arerefluxed in ethanol with 14 g of tin chloride dihydrate to give 2.77 g(63%) of the expected product D (see scheme 1).

MS (ES+), m/z =355

Rf (90/10 CH₂Cl₂/acetone)=0.37

m.p.=167° C.

¹H NMR (DMSO, 400 MHz), 8.3 ppm (1H, t); 8.0 ppm (2H, d); 7.1 ppm (2H,d); 4.4 ppm (2H, q); 4.0 ppm (2H, d); 3.85 ppm (3H, s); 1.8 ppm (2H, m);1.4 ppm (9H, s); 0.85 ppm (3H, t)

Example 881-Ethyl-3-methyl-5-(4-hydroxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide

(R1=methyl; R2=ethyl; R3=4-hydroxyphenyl)

0.4 g (1.24 mmol) of1-ethyl-3-methyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidene-cyanamideis refluxed in dichloromethane with 31 ml of a molar solution of BBr₃ indichloromethane to give 0.14 g (37%) of the expected product.

MS (ES+) m/z=309

m.p.=300° C.

Rf (90/10 CH₂Cl₂/MeOH)=0.55

¹H NMR (DMSO, 400 MHz), 10.15 ppm (1H, s); 9.45 ppm (1H, bs); 8.0 ppm(2H, d); 6.9 ppm (2H, d); 4.45 ppm (2H, q); 4.1 ppm (2H, bs); 2.3 ppm(3H, s); 1.35 ppm (3H, t);

Example 89(±)3-sec-Butyl-1-ethyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=sec-butyl; R2=ethyl; R3=4-methoxyphenyl)

Step 7:

According to M10, 3.38 g (14 mmol) of2-ethyl-5-sec-butyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) arereacted with 2.82 g (14 mmol) of 2-amino-1-(4-methoxyphenyl)ethanonehydrochloride to give 4.69 g (86%) of an amide of type C (see scheme 1).

MS (ES+), m/z=389

¹H NMR (CDCl₃, 400 MHz), 8.0 ppm (2H, d); 7.7 ppm (1H, t); 7.0 ppm (2H,d); 4.95 ppm (2H, d); 4.3 ppm (2H, q); 3.9 ppm (3H, s); 3.4 ppm (1H, m);1.85 ppm (1H, m); 1.65 ppm (1H, m); 1.5 ppm (3H, t); 1.3 ppm (3H, d);0.9 ppm (3H, t)

Step 8:

According to M12, 4.69 g (12 mmol) of the amide C (see scheme 1) arerefluxed in ethanol with 13.6 g of tin chloride dihydrate to give 2.85 g(69%) of the expected product D (see scheme 1).

MS (ES+), m/z=341

¹H NMR (DMSO, 400 MHz), 8.25 ppm (1H, t); 8 ppm (2H, d); 7.05 ppm (2H,d); 4.45 ppm (2H, q); 4 ppm (2H, d); 3.8 ppm (3H, s); 3 ppm (1H, m);1.75 ppm (1H, m); 1.65 ppm (1H, m); 1.35 ppm (3H, t); 1.25 ppm (3H, d);0.8 ppm (3H, t)

Rf (90/10 CH₂Cl₂/acetone)=0.29

m.p.=50° C.

Example 90(±)3-sec-Butyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=sec-butyl; R2=propyl; R3=4-methoxy-phenyle)

Step 7:

According to M10, 3.57 g (14 mmol) of5-sec-butyl-4-nitro-2-propyl-2H-pyrazole-3-carboxylic acid (A) arereacted with 2.82 g (14 mmol) of 2-amino-1-(4-methoxyphenyl)ethanonehydrochloride to give 4.77 g (85%) of an amide of type C (see scheme 1).

MS (ES+), m/z=403

¹H NMR (CDCl₃, 400 MHz), 8.0 ppm (2H, d); 7.7 ppm (1H, t); 7.0 ppm (2H,d); 4.95 ppm (2H, d); 4.2 ppm (2H, q); 3.9 ppm (3H, s),; 3.4 ppm (1H,m); 1.9 ppm (3H, m); 1.6 ppm (1H, m); 1.3 ppm (3H, d); 0.9 ppm (6H, m)

Step 8:

According to M12, 4.77 g (12 mmol) of the amide C (see scheme 1) arerefluxed in ethanol with 13.4 g of tin chloride dihydrate to give 2.37 g(56%) of the expected product D (see scheme 1).

Rf (90/10 CH₂Cl₂/acetone)=0.37

m.p.=85° C.

MS (ES+), m/z=355

¹H NMR (DMSO, 400 MHz), 8.25 ppm (1H, t); 8.0 ppm (2H, d); 7.05 ppm (2H,d); 4.4 ppm (2H, q); 4.0 ppm (2H, m); 3.8 ppm (3H, s); 3.0 ppm (1H, m);1.75 ppm (3H, m); 1.65 ppm (1H, m); 1.25 ppm (3H, d); 0.8 ppm (6H, m)

Example 911-Ethyl-3-methyl-5-(3,4,5-trimethoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=3,4,5-trimethoxyphenyl)

Step 7:

According to M10, 0.153 g (0.77 mmol) of2-ethyl-5-methyl-4-nitro-2H-pyrazole-3-carboxylic acid (A) is reactedwith 0.246 g (0.77 mmol) of 2-amino-1-(3,4,5-trimethoxyphenyl)-ethanonehydrochloride (78%) (J. Org. Chem., 38, 3571-3575, 1973) to give 0.313 g(83%) of an amide of type C (see scheme 1).

Rf (CH₂Cl₂/MeOH 95/5)=0.78

¹H NMR (CDCl₃, 400 MHz), 8.0 ppm (1H, bs); 7.2 ppm (2H, d); 5.0 ppm (2H,d); 4.3 ppm (2H, q); 3.9 ppm (9H, s); 2.6 ppm (3H, s); 1.5 ppm (3H, t)

Step 8:

According to M12, 0.26 g (0.64 mmol) of the amide C (see scheme 1) isrefluxed in ethanol with 0.72 g of tin chloride dihydrate to give 0.13 g(57%) of the expected product D (see scheme 1).

Rf (95/5 CH₂Cl₂/MeOH)=0.52

m.p.=208° C.

MS (ES+), m/z=359

¹H NMR (DMSO, 400 MHz), 8.25 ppm (1H, t); 7.3 ppm (2H, s); 4.45 ppm (2H,q); 4.0 ppm (2H, d); 3.9 ppm (6H, s); 3.7 ppm (3H, s); 2.3 ppm (3H, s);1.35 ppm (3H, t)

Example 921-Ethyl-5-(3-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=3-hydroxyphenyl)

0.4 g (1.34 mmol) of1-ethyl-5-(3-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-oneis refluxed in dichloromethane with 33.5 ml of a molar solution of BBr₃in dichloromethane to give 0.075 g (20%) of the expected product.

MS (ES+) m/z=285

m.p.=204° C.

Rf (90/10 CH₂Cl₂/MeOH)=0.55

¹H NMR (DMSO, 400 MHz), 9.65 ppm (1H, s); 8.25 ppm (1H, m); 7.45 ppm(2H, m); 7.3 ppm (1H, m); 6.9 ppm (1H, m); 4.4 ppm (2H, q); 3.95 ppm(2H, d); 2.3 ppm (3H, s); 1.35 ppm (3H, t)

Example 931-Ethyl-5-(2-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=methyl; R2=ethyl; R3=2-hydroxyphenyl)

0.4 g (1.34 mmol) of1-ethyl-5-(2-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-oneis refluxed in dichloromethane with 33.5 ml of a molar solution of BBr₃in dichloromethane to give 0.070 g (19%) of the expected product.

MS (ES+) m/z=285

m.p.=220° C.

Rf (90/10 CH₂Cl₂/MeOH)=0.7

¹H NMR (DMSO, 400 MHz), 14.0 ppm (1H, s); 8.35 ppm (1H, m); 7.8 ppm (1H,m); 7.4 ppm (1H, m); 7.0 ppm (2H, m); 4.45 ppm (2H, q); 4.2 ppm (2H, d);2.3 ppm (3H, s); 1.35 ppm (3H, t)

Example 941-Ethyl-5-(4-hydroxyphenyl)-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=isopropyl; R2=ethyl; R3=4-hydroxyphenyl)

0.5 g (1.53 mmol) of1-ethyl-5-(4-methoxy-phenyl)-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-oneis refluxed in dichloromethane with 38 ml of a molar solution of BBr₃ indichloromethane to give 0.23 g (48%) of the expected product.

MS (ES+) m/z=313

m.p.=230° C.

Rf (90/10 CH₂Cl₂/MeOH)=0.27

¹H NMR (DMSO, 400 MHz), 10.0 ppm (1H, s); 8.2 ppm (1H, t); 7.85 ppm (2H,d); 6.85 ppm (2H, d); 4.4 ppm (2H, q); 3.9 ppm (2H, d); 3.2 ppm (1H, m);1.35 ppm (3H, t); 1.3 ppm (6H, d)

Example 955-(4-Hydroxyphenyl)-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=isopropyl; R2=propyl; R3=4-hydroxyphenyl)

0.5 g (1.47 mmol) of5-(4-methoxyphenyl)-3-isopropyl-1-propyl-5-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-oneis refluxed in dichloromethane with 37 ml of a molar solution of BBr₃ indichloromethane to give 0.2 g (42%) of the expected product.

MS (ES+) m/z=327

m.p.=230° C.

Rf (90/10 CH₂Cl₂/MeOH)=0.38

¹H NMR (DMSO, 400 MHz), 10.0 ppm (1H, s); 8.2 ppm (1H, t); 7.85 ppm (2H,d); 6.85 ppm (2H, d); 4.4 ppm (2H, q); 3.9 ppm (2H, d); 3.2 ppm (1H, m);1.8 ppm (2H, m); 1.3 ppm (6H, d); 0.85 ppm (3H, t)

Example 963-tert-Butyl-1-ethyl-5-(4-hydroxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one

(R1=tert-butyl; R2=ethyl; R3=4-hydroxyphenyl)

0.5 g (1.47 mmol) of1-tert-butyl-5-(4-methoxyphenyl)-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-oneis refluxed in dichloromethane with 1.4 ml of BBr₃ to give 0.29 g (60%)of the expected product.

MS (ES+) m/z=327

m.p.=264° C.

Rf (90/10 CH₂Cl₂/MeOH)=0.4

¹H NMR (DMSO, 400 MHz), 10.0 ppm (1H, s); 8.2 ppm (1H, t); 7.85 ppm (2H,d); 6.85 ppm (2H, d); 4.4 ppm (2H, q); 3.9 ppm (2H, d); 1.4 ppm (9H, s);1.3 ppm (3H, t)

Example 973-Ethoxymethyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-one

(R1=ethoxymethyl ; R2=ethyl; R3=phenyl)

Step 19:

8.1 g (22 mmol) of compound R (see scheme 3) are reacted with 49 ml ofethylene glycol and 0.81 g (4.3 mmol) of para-toluenesulphonic acidmonohydrate in 170 ml of toluene. After 48 hours, about 40 ml of waterhave been removed (Dean-Stark apparatus). The reaction mixture istreated with saturated NaHCO₃ solution and water and the phases are thenallowed to separate by settling. The organic phase is dried over Na₂SO₄and concentrated. The oil obtained is chromatographed on silica with an80/20 cyclohexane/EtOAc mixture to give 6.6 g (73%) of the expectedcompound S (see scheme 3).

Rf (70/30 cyclohexane/EtOAc)=0.28

MS (ES+), m/z=418.9

¹H NMR (CDCl₃, 400 MHz), 7.3-7.55 ppm (6H, m); 4.4-4.5 ppm (4H, m); 4.1ppm (2H, q); 3.8 ppm (4H, m); 1.5 ppm (3H, t); 1.4 ppm (3H, t)

Step 20:

1.5 g (3.6 mmol) of compound S (see scheme 3) are reacted with 4.3 ml(8.6 mmol) of a 2M solution of lithium borohydride in THF, in 25 ml ofanhydrous THF. After 12 hours at room temperature, the reaction mixtureis extracted with water and diethyl ether. The organic phase is driedover Na₂SO₄ and concentrated to give 1.2 g (96%) of the expectedcompound T (see scheme 3).

Rf (95/5 CH₂Cl₂/MeOH)=0.17

MS (ES+), m/z=347

¹H NMR (DMSO, 400 MHz), 8.65 ppm (1H, m); 7.3-7.5 ppm (5H, m); 4.9 ppm(1H, t); 4.4 ppm (2H, d); 4.3 ppm (2H, q); 4.05 ppm (2H, t); 4.0 ppm(2H, s); 3.8 ppm (2H, t); 3.7 ppm (2H, d); 1.2 ppm (3H, t)

Step 21:

0.3 g (0.9 mmol) of compound T (see scheme 3) is reacted with 15 ml ofethanol and 15 ml of 6N HCl at 80° C. After 12 hours, the reactionmixture is concentrated and the residue obtained is extracted with waterand dichloromethane. The organic phase is dried over Na₂SO₄ andconcentrated and then chromatographed on silica using an elutiongradient of from 100% dichloromethane to a 95/5 dichloromethane/MeOHmixture to give 0.023 g (8.5%) of the compound D (see scheme 3)(RB=ethyl).

Rf (95/5 CH₂Cl₂/MeOH)=0.27

MS (ES+), m/z=313

¹H NMR (CDCl₃, 400 MHz), 7.9 ppm (2H, m); 7.45 ppm (3H, m); 6.0 ppm (1H,m); 4.75 ppm (2H, s); 4.6 ppm (2H, q); 4.15 ppm (2H, d); 3.65 ppm (2H,q); 1.5 ppm (3H, t); 1.25 ppm (3H, t)

Evaluation of the Biological Activity of the Compounds of the PresentInvention

Evaluation of the in vitro Activity of the Compounds of the Examples

The capacity of the compounds of formula (I) of the invention to inhibitcyclic nucleotide phosphodiesterases is evaluated by measuring theirIC₅₀ (concentration needed to inhibit 50% of the enzymatic activity). Inthe case of PDE4 enzymes, this value is compared to the IC₅₀ value forrolipram, a reference inhibitor for PDE4 enzymes.

The type 4 phosphodiesterases are obtained from a cytosolic preparationextracted from a cell line of human origin, U937, according to themethod adapted from T. J. Torphy et al., 1992, J. Pharm. Exp. Ther. 263:1195-1205.

The other types of phosphodiesterase are obtained during a partialpurification by FPLC on a Mono Q column (anion exchange column)according to a method adapted from Lavan B. E., Lakey T., Houslay M. D.Biochemical Pharmacology, 1989, 38(22), 4123-4136, and Silver P. J etal., 1988, Eur. J. Pharmacol. 150: 85-94, either starting with celllines of human origin for PDE1 (monocyte line TPH1) and PDE5 (linederived from an adenocarcinoma MCF7), or starting with dog aorta forPDE3, or, for human PDE3A, starting with a cloning of genes in SF21insect cells into baculovirus, according to the method adapted fromLuckow, V. A. et al., 1991 in Recombinant DNA Technology &Applications., eds. Prokop, Bajpai, R. K. & Ho, C. S., pp 97-152.

The measurement of the enzymatic activity for the various types of PDE,and in particular the PDE4 enzymes, is carried out according to a methodadapted from W. J. Thomson et al. 1979, Advances in Cyclic NucleotideResearch, Vol. 10: 69-92, ed. G. Brooker et al. Raven Press, NY.

For the determination of the IC₅₀ value, the enzymatic activity ismeasured in the presence of the inhibitor in a concentration range from0.1 to 100 μM.

Table 1 below illustrates the inhibitory activity of PDE4 compared withthat of rolipram on an enzyme preparation obtained from the U937 line.

TABLE 1 IC₅₀ Example (μM) 1 0.0049 2 0.00098 3 0.00012 4 0.0084 5 0.39 60.42 7 0.13 8 0.21 9 0.15 10 1.29 11 0.12 12 0.10 13 0.13 14 0.081 150.52 16 0.42 17 0.0059 18 0.10 19 0.087 20 0.099 21 0.0026 22 0.028 230.042 24 0.078 25 0.0024 26 0.0056 27 0.0038 28 0.090 29 0.33 30 0.30 310.19 32 0.13 33 0.11 34 0.0047 35 0.00070 36 0.00039 37 0.00097 38 0.6539 0.0091 40 0.0082 41 0.011 42 0.010 43 0.048 44 0.0011 45 0.0026 460.00084 47 0.021 48 0.0081 49 0.032 50 0.016 51 0.06 52 0.00065 53 0.2654 0.24 55 0.0017 56 0.50 57 0.00013 58 0.14 59 0.51 60 0.58 61 0.007962 0.26 63 0.0050 64 0.0046 65 0.0015 66 0.00063 67 0.0010 68 0.0062 690.013 70 0.011 71 0.035 72 0.0018 73 0.00073 74 0.0054 75 0.0049 760.0082 77 0.21 78 0.021 79 0.011 80 0.00022 81 0.00054 82 0.062 83 0.1084 0.060 85 0.20 86 0.31 87 0.041 88 0.0021 89 0.033 90 0.193 91 0.90 920.092 93 0.0074 94 0.0021 95 0.015 96 0.0049 97 1.58 Rolipram 0.859

Examination of the results of Table 1 shows that the products of theinvention tested in the study generally inhibit the PDE4 enzyme of humanorigin much more effectively than rolipram, and in certain cases theseproducts are between 3 000 and 4 000 times more active than rolipram.

Evaluation of the in vivo Activity of the Compounds of the Invention

in vivo TNFα Model in Wistar Rats

TNFα is a cytokine which plays a central role in the mechanisms ofinflammation. Its production can be induced by an injection oflipopolysaccharide (LPS). It has been shown that the increase inintracellular cAMP, produced in particular by PDE4 inhibitors, decreasesthe production of TNFα in in vitro and in vivo models. It is thus amatter here of quantifying in vivo the anti-inflammatory potential ofthe compounds of the invention, administered orally (p.o.) by measuringthe inhibition of the production of TNFα in the plasma of rats, theserats having received an intraperitoneal (i.p.) injection oflipopolysaccharide (LPS). The treatment with the compounds of theinvention or the vehicle are [sic] administered orally to male Wistarrats, 30 min before the injection of LPS. The rats are sacrificed 90 minafter the stimulation with LPS, the blood is collected onto EDTA and theTNFα concentration is measured in each plasma sample. Most of thecompounds of the invention and in particular the compounds hereinbelowshowed excellent activity in this model.

-   1-Ethyl-5-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-(4-Aminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Methyl-5-phenyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-(2-Hydroxyethyl)-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-thione,-   1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-one,-   5-(3-Aminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,-   1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-thione,-   5-(4-Aminophenyl)-3-tert-butyl-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-5-(4-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-Cyclohexyl-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-methyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-one,-   5-tert-Butyl-1-ethyl-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-one,-   5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-one,-   4-(1-Ethyl-3-isopropyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,-   5-(2,4-Dimethoxyphenyl)-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   5-tert-Butyl-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-one,-   3-Isopropyl-1-propyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   4-(3-Isopropyl-8-oxo-1-propyl-1,6,7,8-tetrahydro-pyrazolo-[4,3-e][1,4]diazepin-5-yl)benzonitrile,-   3-tert-Butyl-1-ethyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   4-(3-tert-Butyl-1-ethyl-8-oxo-1,6,7,8-tetrahydropyrazolo-[4,3-e][1,4]diazepin-5-yl)benzonitrile,-   1-Ethyl-3-methyl-5-phenyl-1,6-dihydropyrazolo-[4,3-e][1,4]diazepin-8-ylcyanamide,-   1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-ylidenecyanamide,-   (±)3-sec-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-one,-   (±)3-sec-Butyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   (±)3-sec-Butyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-one,-   3-Cyclohexyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo-[4,3-e][1,4]diazepin-8-one.    References-   Chen, Y. L., Le Vraux, V., Giroud, J. P. and Chauvelot-Moachon L.    (1994). Anti-tumor necrosis factor properties of non-peptide drugs    in acute-phase responses. Eur. J. Pharmacol., 271 (2-3), 319-27.-   Prabhakar, U., Lipshutz, D., O'Leary Barthus, J., Slivjak, J., Smith    III E. F., Lee, J. C. and Esser K. M. (1994).-   Characterization of cAMP-dependent inhibition of LPS-induced TNFα    production by rolipram, a specific phosphodiesterase IV (PDE IV)    inhibitor. Int. J. Immunopharmacol., 16 (10), 805-816.    Model of Eosinophilia in Rats

The studies carried out using this experimental model have the aim ofevaluating the inhibitory activity of the compounds of the invention onthe afflux of inflammatory cells and in particular of eosinophils in thelumen of the bronchotracheal tree of rats. Eosinophils play a major rolein the physiopathology of asthma in man by releasing into the pulmonaryparenchyma pro-inflammatory mediators such as leukotrienes, specificproteins and enzymes (ECP, EPO, MBP) and cytokines. The massiverecruitment of this cell type in the aerial pathways of an asthmaticleads to a gradual degradation of the pulmonary tissue, which explainsthe bronchial hyperreactivity, the chronic aspect of the disease and theexacerbations in the absence of treatment. This model uses Brown Norwayrats, which have the particular feature of producing, like atopicpatients, high levels of immunoglobulin E (IgE) in response to asensitization by an antigen. The protocol used involves twosensitizations with ovalbumin with a fourteen-day interval, followed bya challenge seven days later with an ovalbumin aerosol. 48 hours afterthe antigenic challenge, the animals undergo bronchoalveolar lavageunder anaesthesia in order to collect the infiltrate of inflammatorycells on the lungs. These cells are then counted and differentiatedaccording to morphological criteria. The products of the invention areadministered orally, 1 hour before the antigenic challenge. Most of thecompounds of the present invention tested in this model alsodemonstrated excellent activity.

References

-   Corrigan et al. (1992) Immunology today 13: 501-507-   Elwood et al. (1995) Inflamm Res 44: 83-86    Model of Neutrophilia in Mice

The studies carried out using this experimental protocol have the aim ofevaluating the modulatory action of the compounds of the invention onthe afflux of pro-inflammatory cells (early phase) in the lumen of thebronchotracheal tree of mice. This cellular afflux follows a stimulationmimicking a bacterial infection (bacterial lipopoly-saccharide or LPS).This early inflammatory stage is the result of a combination of events,the main ones of which are the synthesis and release of stimulatoryfactors (TNFα^(i)) and chemotactic factors (IL-8^(ii)), the increase invascular permeability in the bronchotracheal microcirculation, and theinfiltration of polymorphonuclear neutrophils, concomitant with theexudation of plasma proteins into the pulmonary tissues.

This pathological process is found in chronic obstructivebronchopneumopathy (or COPD), in which the neutrophil, in concert withthe macrophage, plays a key role in establishing the amplification ofthe recruitment of the neutrophils themselves, but also in thedestructuring of pulmonary tissues (decline in pulmonary functions), thehypersecretion of bronchotracheal mucus (congestion of the aerialpathways), tissue inflammation (release of inflammatory mediators andfree radicals) and increase in the basal tonus of pulmonary smoothmuscle fibres (chronic respiratory gene). Most of the compounds of thepresent invention tested in this model demonstrated excellent activity.

References

-   ^(i)SUTER P. M., SUTER S., GIRARDIN E., ROUX-LOMBARD P., GRAU G. E.    and DAYER J. -M. 1992. High bronchoalveolar levels of tumor necrosis    factor and its inhibitors, interleukin-1, interferon and elastase,    in patients with adult respiratory distress syndrome after trauma,    shock or sepsis. Am. Rev. Respir. Dis. 145: 1016-1022.-   ^(ii)MARTIN T. R. and GOODMAN R. B. 1999. The role of chemokines in    the pathology of the acute respiratory distress syndrome. Chapter 6    in Chemokines in disease: Biology and clinical research edited    by: C. A. Hebert, Humana Press Inc., Totowa, N.J.-   ^(iii)REPINE J. E. and BEEHLER C. J. 1991. Neutrophils and the adult    respiratory distress syndrome: two interlocking perspectives. Am.    Rev. Respir. Dis. 144: 251-252.    Jejunal Inflammation and Septic Shock Induced by E. coli    Lipopolysaccharide in Rats

Lipopolysaccharide (LPS) from Escherichia coli administeredintravenously to fasted male Wistar rats induces an inflammation of thejejunum two hours later.

Male Wistar rats (200-280 g), fasted (18 h), from the Sté Janvier,Le-genest-St Isle, Mayenne, France are used in these experiments.

The compounds to be tested are suspended in a vehicle (1%methylcellulose (95% v/v)+polyethylene glycol 400 (5% v/v)). They arethen administered orally (5 ml/kg) using a stainless steel probe, onehour before administration of the inducing agent (LPS). The groups ofanimals are distributed in the following manner:

-   -   Negative controls: p.o. vehicle+serum i.v. physiological saline    -   Positive controls: p.o. vehicle+LPS    -   Treated: p.o. compound+LPS

The lipopolysaccharide (LPS), endotoxin from Escherichia coli (serotype0127:B8), is then injected intravenously (caudal vein) at a dose of 40mg/kg (5 ml/kg) to conscious rats maintained under slight support.

Two hours later, the animals are sacrificed, the abdomen is opened and a10 cm section of jejunum (30th to 40th after the pylorus) is taken, cutin the direction of its length, mopped and weighed.

The macroscopic attack is evaluated (0=none, 1=slight, 2=moderate,3=severe).

After weighing, the segment is fixed onto a flat surface andmeasurements of the percentage of hyperhemiated surfaces are made usingan image analyser.

Immediately after analysis, the tissue is deposited in 10 ml of Drabkinreagent to determine the haemoglobin content of the tissue (calorimetricassay 24 hours later). Most of the compounds of the present inventiontested in this model demonstrated excellent activity.

-   Lipopolysaccharide (LPS): Sigma, reference L-3880, France.-   Polyethylene glycol: M.W. 400, Sigma, reference P-3265-   Haemoglobin content of the jejunum: Sigma kit, Total haemoglobin,    reference 525-A.    Main Reference:-   Cardelus Ignasi et al. European Journal of Pharmacology 299 (1996);    153-159

1. A method of treating chronic obstructive bronchopneumopathy or asthmain a mammal, which method comprises administering to said mammal acompound of formula:

in which: R1 is: hydrogen; linear or branched (C₁-C₆)alkyl;(C₃-C₆)cycloalkyl; (C₁-C₆)alkyl(C₃-C₆)cycloalkyl; (C₅-C₁₀)aryloptionally interrupted with one nitrogen, oxygen or sulphur;(C₆-C₁₀)arylalkyl optionally interrupted with one nitrogen, oxygen orsulphur; (C₆-C₁₀)alkylaryl optionally interrupted with one nitrogen,oxygen or sulphur; linear or branched (C₂-C₆)alkenyl; or(CH₂)_(n)OR_(B), (CH₂)_(n)CF₃, (CH₂)_(n)C(O)R_(B), (CH₂)_(n)COOR_(B),(CH₂)_(n)OC(O)R_(A), (CH₂)_(n)SR_(B), (CH₂)_(n)C(S)R_(B),(CH₂)_(n)C(S)OR_(B), (CH₂)_(n)C(S)SR_(B), (CH₂)_(n)NR_(B)R_(C),(CH₂)_(n)C(O)NR_(B)R_(C), (CH₂)_(n)NR_(C)C(O)R_(B),(CH₂)_(n)NR_(D)C(O)NR_(D)R_(B) or (CH₂)_(n)Z; R_(A) is linear orbranched (C₁-C₆)alkyl; (C₃-C₆)cycloalkyl; (C₁-C₆)alkyl(C₃-C₆)cycloalkyl;(C₅-C₁₀)aryl optionally interrupted with one nitrogen, oxygen orsulphur; (C₆-C₁₀)arylalkyl optionally interrupted with one nitrogen,oxygen or sulphur; (C₆-C₁₀)alkylaryl optionally interrupted with onenitrogen, oxygen or sulphur; or linear or branched (C₂-C₆)alkenyl; R_(B)and R_(C), which are identical or different, are: hydrogen; linear orbranched (C₁-C₆)alkyl; (C₃-C₆)cycloalkyl; (C₁-C₆)alkyl(C₃-C₆)cycloalkyl;(C₅-C₁₀)aryl optionally interrupted with one nitrogen, oxygen orsulphur; (C₆-C₁₀)arylalkyl optionally interrupted with one nitrogen,oxygen or sulphur; (C₆-C₁₀)alkylaryl optionally interrupted with onenitrogen, oxygen or sulphur; or linear or branched (C₂-C₆)alkenyl; itbeing possible for R_(B) and R_(C) to form ring containing from 5 to 7atoms which can include one to three sulphur, nitrogen or oxygen; R_(D)is hydrogen or linear or branched (C₁-C₆)alkyl; Z is a halogen; and n is0, 1, 2, 3 or 4; R2 is: linear or branched (C₁-C₆)alkyl;(C₁-C₆)alkyl(C₃-C₆)cycloalkyl; (C₃-C₆)cycloalkyl; (C₅-C₁₀)aryloptionally interrupted with one nitrogen, oxygen or sulphur;(C₆-C₁₀)alkylaryl optionally interrupted with one nitrogen oxygen orsulphur; linear or branched (C₂-C₆)alkenyl; or (CH₂)_(m)OR_(B),(CH₂)_(n)CF₃, (CH₂)_(m)C(O)R_(B), (CH₂)_(m)COOR_(B),(CH₂)_(m)OC(O)R_(A), (CH₂)_(m)SR_(B), (CH₂)_(m)C(S)R_(B),(CH₂)_(m)C(S)OR_(B), (CH₂)_(m)C(S)SR_(B), (CH₂)_(m)NR_(B)R_(C),(CH₂)_(m)C(O)NR_(B)R_(C), (CH₂)_(m)NR_(C)C(O)R_(B),(CH₂)_(m)NR_(D)C(O)NR_(D)R_(B) or (CH₂)_(m)Z; m is 0, 1, 2, 3 or 4; R3is: hydrogen; linear or branched (C₁-C₆)alkyl; (C₃-C₆)cycloalkyl;(C₁-C₆)alkyl(C₃-C₆)cycloalkyl; (C₅-C₁₀)aryl optionally interrupted withone nitrogen, oxygen or sulphur; (C₆-C₁₀)arylalkyl optionallyinterrupted with one nitrogen, oxygen or sulphur; (C₆-C₁₀)alkylaryloptionally interrupted with one nitrogen, oxygen or sulphur; linear orbranched (C₂-C₆)alkenyl; or (CH₂)_(n)OR_(B), (CH₂)_(n)CF₃,(CH₂)_(n)C(O)R_(B), (CH₂)_(n)COOR_(B), (CH₂)_(n)OC(O)R_(A),(CH₂)_(n)SR_(B), (CH₂)_(n)C(S)R_(B), (CH₂)_(n)C(S)OR_(B),(CH₂)_(n)C(S)SR_(B), (CH₂)_(n)NR_(B)R_(C), (CH₂)_(n)C(O)NR_(B)R_(C),(CH₂)_(n)NR_(C)C(O)R_(B), (CH₂)_(n)NR_(D)C(O)NR_(D)R_(B) or (CH₂)_(n)Z;the aryl, arylalkyl and alkylaryl are unsubstituted or substituted onthe aryl with 1, 2 or 3: halogen, hydroxyl, NO, NO₂, CN, (C₁-C₄)alkoxy,(CH₂)_(n)OR_(B), (CH₂)_(n)NR_(B)R_(C), (CH₂)_(n)NC(O)R_(B),(CH₂)_(n)HNSO₂R_(B), (CH₂)_(n)N(SO₂R_(B))₂, CO₂R_(B), CF₃ or

 and the dotted line is absent such that the bond between W and thecarbon atom at position 5 is a single bond and W is —NH—, or the dottedline is present such that the bond between W and the carbon atom atposition 5 is a double bond and W is —N—; X is S, O, N—CN or N—R_(B); oran oxide, tautomer or optical isomer thereof; with the proviso that whenR1 is methyl, R2 is ethyl, W is —N—, X is an oxygen atom and the dottedline is present, then R3 is neither an unsubstituted phenyl group nor aphenyl group bearing a fluorine atom in an ortho position as solesubstituent, a pharmceutically acceptable salt thereof, or apharmaceutical composition comprising said compound or saidpharmaceutically acceptable salt thereof.
 2. A method of claim 1comprising a compound of formula I;

in which R1, R2, R3 and X are as defined in claim 1, W is —N— and thedotted line is present.
 3. A method of claim 1 comprising a compound offormula II;

in which; R1 is linear or branched (C₁-C₆)alkyl; (C₃-C₆)cycloalkyl;(C₁-C₆)alkyl(C₃-C₆)cycloalkyl; (C₅-C₁₀)aryl optionally interrupted withwith one nitrogen, oxygen or sulphur; (C₆-C₁₀)arylalkyl optionallyinterrupted with one nitrogen, oxygen or sulphur; (C₆-C₁₀)alkylaryloptionally interrupted with one nitrogen, oxygen or sulphur; linear orbranched (C₂-C₆)alkenyl; (CH₂)_(n)OR_(B), (CH₂)_(n)CF₃,(CH₂)_(n)C(O)R_(B), (CH₂)_(n)COOR_(B), (CH₂)_(n)OC(O)R_(A),(CH₂)_(n)SR_(B), (CH₂)_(n)NR_(B)R_(C), (CH₂)_(n)C(O)NR_(B)R_(C),(CH₂)_(n)NR_(C)C(O)R_(B) or (CH₂)_(n)Z; R_(A) is linear or branched(C₁-C₆)alkyl; (C₃-C₆)cycloalkyl; (C₁-C₆)alkyl(C₃-C₆)cycloalkyl;(C₅-C₁₀)aryl optionally interrupted with one from nitrogen, oxygen orsulphur; (C₆-C₁₀)arylalkyl optionally interrupted with one nitrogen,oxygen or sulphur; (C₆-C₁₀)alkylaryl optionally interrupted with onenitrogen, oxygen or sulphur; linear or branched (C₂-C₆)alkenyl; R2 islinear or branched (C₁-C₄)alkyl; (CH₂)_(n)CF₃; methylcyclopropyl; linearor branched (C₂-C₆)alkenyl; or (CH₂)_(m)OR_(B) and (CH₂)_(m)CO₂R_(B); mis 1, 2 or 3; R3 is linear or branched (C₁-C₆)alkyl; (C₃-C₆)cycloalkyl;(C₁-C₆)alkyl(C₃-C₆)cycloalkyl (C₅-C₁₀)aryl optionally interrupted withone nitrogen, oxygen or sulphur; (C₆-C₁₀)arylalkyl optionallyinterrupted with one nitrogen, oygen or sulphur; (C₆-C₁₀)alkylaryloptionally interrupted with one nitrogen, oxygen or sulphur; linear orbranched (C₂-C₆)alkenyl; (CH₂)_(n)OR_(B), (CH₂)_(n)C(O)R_(B),(CH₂)_(n)COOR_(B), (CH₂)_(n)OC(O)R_(A), CH₂)_(n)NR_(B)R_(C),(CH₂)_(n)C(O)NR_(B)R_(C) and (CH₂)_(n)NR_(C)C(O)R_(B); and, X is O, S orNCN.
 4. A method of claim 1 in which: R1 is linear or branched(C₁-C₆)alkyl; (C₃-C₆)cycloalkyl; (C₁-C₆)alkyl(C₃-C₆)cycloalkyl;(C₅-C₁₀)aryl optionally interrupted with one nitrogen, oxygen orsulphur; (C₆-C₁₀)alkylaryl optionally interrupted with one nitrogen,oxygen or sulphur; linear or branched (C₂-C₆)alkenyl; (CH₂)_(n)OR_(B),(CH₂)_(n)C(O)R_(B), (CH₂)_(n)COOR_(B), (CH₂)_(n)OC(O)R_(A),(CH₂)_(n)NR_(B)R_(C), (CH₂)_(n)C(O)NR_(B)R_(C), (CH₂)_(n)NR_(C)C(O)R_(B)or (CH₂)_(n)Z, in which, R_(A) is linear or branched (C₁-C₆)alkyl;(C₅-C₁₀)aryl optionally interrupted with one nitrogn, oxygen or sulphur;or (C₆-C₁₀)alkylaryl optionally interrupted with one nitrogen, oxygen orsulphur; R_(B) and R_(C), which may be identical or different, are:hydrogen; linear or branched (C₁-C₆)alkyl; C₅-C₁₀)aryl optionallyinterrupted with one nitrogen, oxygen or sulphur; (C₆-C₁₀)alkylaryloptionally interrupted with one nitrogen, oxygen or sulphur; R2 islinear or branched (C₁-C₄)alkyl, (CH₂)_(m)OH or (CH₂)_(m)CO₂H; m is 1, 2or 3; R3 is linear or branched (C₁-C₆)alkyl; (C₃-C₆)cycloalkyl;(C₅-C₁₀)cycloalkyl optionally interrupted with one nitrogen, oxegen orsulphur; (C₆-C₁₀)arylalkyl optionally interrupted with one nitrogen,oxygen or sulphur; (C₆-C₁₀)alkylaryl optionally interrupted with onenitrogen, oxygen or sulphur; the aryl, arylalkyl and alkylaryl areunsubstituted or substituted on the aryl with 1, 2 or 3 halogen,hydroxyl, NO, NO₂, CN, (C₁-C₄)alkoxy, (CH₂)_(n)OR_(B),(CH₂)_(n)NR_(B)R_(C), (CH₂)_(n)NC(O)R_(B), CO₂R_(B), CF₃, or

 and X is O, S or NCN.
 5. A method of claim 1 in which: R1 is linear orbranched (C₁-C₄)alkyl; (C₃-C₆)cycloalkyl; (C₁-C₃)alkyl(C₃-C₆)cycloalkyl;R2 is linear or branched (C₁-C₄)alkyl; R3 is linear or branched(C₁-C₄)alkyl; (C₅-C₁₀)aryl optionally interrupted with one nitrogen,oxygen or sulphur, the aryl groups being unsubstituted or substitutedindependently with 1, 2 or 3 NH₂, halogen, methoxy, hydroxyl, CN, CH₃ orCF₃; and, X is O, S or NCN.
 6. A meethod of claim 1 in which: R1 islinear or branched (C₁-C₄)alkyl; R2 is linear or branched (C₁-C₄)alkylor (CH₂)_(n)OH; R3 is linear or branched (C₁-C₄)alkyl,(C₃-C₆)cycloalkyl, phenyl or thienyl, the phenyl and thienyl may beunsubstituted or substituted independently with halogen, hydroxyl,methoxy, NH₂ or CH₃; and X is S or O.
 7. A method of claim 1 whereinsaid compound is1-Ethyl-5-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(4-Bromophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1,3-Dimethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(4-Methoxyphenyl)-1,3-dimethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(4-Bromophenyl)-1,3-dimethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-methyl-5-naphth-2-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(3-Chlorothien-2-yl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,Methyl3-(1-ethyl-3-methyl-8-oxo-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)propanoate,1-Ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(4-Chlorophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(4-Aminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(4-fluorophenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(3-Bromophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Methyl-5-phenyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Isopropyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,(±)1-Ethyl-3-methyl-5-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-(2-Hydroxyethyl)-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,1-Ethyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(3-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(2-Aminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(2-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-methyl-5-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,isomer 1,1-Ethyl-3-methyl-5-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,isomer 2,3-Methyl-5-phenyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,1-Ethyl-3-methyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(3-Aminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyt-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,5-(4-Aminophenyl)-3-tert-butyl-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(4-Aminophenyl)-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(4-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(4-Aminophenyl)-3-methyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Methyl-5-phenyl-1-(2,2,2-trifluoroethyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1,5-Diethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-Cyclohexyl-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-methyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,(±)1-Ethyl-3-methyl-5-pyrid-4-yl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-tert-Butyl-1-ethyl-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(4-Diethylaminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,N-[4-(1-Ethyl-3-methyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)phenyl]acetamide,4-(1-Ethyl-3-methyl-8-oxo-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8one,1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,4-(1-Ethyl-3-isopropyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,1-Ethyl-3-isopropyl-5-(4-pyrrolidin-1-yl-phenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(2,4-Dimethoxyphenyl)-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-tert-Butyl-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Isopropyl-1-propyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,4-(3-Isopropyl-8-oxo-1-propyl-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,3-Isopropyl-1-propyl-5-(4-pyrrolidin-1-yl-phenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(2,4-Dimethoxyphenyl)-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3,5-Di-tert-butyl-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,4-(3-tert-Butyl-1-ethyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,3-tert-Butyl-1-ethyl-5-(4-pyrrolidin-1-yl-phenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-5-(2,4-dimethoxyphenyl)-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3,5-Di-tert-butyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-propyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,4-(3-tert-Butyl-8-oxo-1-propyl-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,3-tert-Butyl-1-propyl-5-(4-pyrrolidin-1-yl-phenyl)-6,7-dihydro-1H-pyrazol[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-5-(2,4-dimethoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,1-Ethyl-3-methyl-5-pyrid-3-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-methyl-5-pyrid-2-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-methyl-5-phenyl-1,6-dihydropyrazolo[4,3-e][1,4]diazepin-8-ylcyanamide,N-[4-(1-Ethyl-3-methyl-8-oxo-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)phenyl]-(phenylsulphonyl)benzenesulphonamide,(1-Ethyl-3-methyl-5-phenyl-1,6-dihydropyrazolo[4,3-e][1,4]diazepin-8-yl)methylamine,1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,1-Cyclopentyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Cyclopropylmethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Cyclobutylmethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Allyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-methyl-5-(4-trifluoromethylphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-isopropyl-5-(4-trifluoromethylphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-(4-trifluoromethylphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Isopropyl-1-propyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,3,5-Di-tert-butyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,5-tert-Butyl-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,(±)3-sec-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,(±)3-sec-Butyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,(±)3-sec-Butyl-5-phenyl-1-propyl-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,(±)3-sec-Butyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexyl-1-ethyl-5-phenyl-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexyl-5-phenyl-1-propyl-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexylmethyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexylmethyl-5-phenyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexytmethyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexylmethyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-8-oxo-5-phenyl-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-3-carboxylicacid ethyl ester,5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,1-Ethyl-3-isopropyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,1-Ethyl-5-(4-methoxyphenyl)-3-methyl-8,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,3-Isopropyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-][1,4]diazepin-8-one,1-Ethyl-5-(4-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,(±)3-sec-Butyl-1-ethyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,(±)3-sec-Butyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-methyl-5-(3,4,5-trimethoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(3-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(2-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-methyl-5-(2,3,4-trimethoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3,5-diphenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(4-hydroxyphenyl)-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(4-Hydroxyphenyl)-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-(4-hydroxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(2,6-Dimethoxyphenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,or3-Ethoxymethyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one.8. A method of claim 1 wherein said compound is1-Ethyl-5-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(4-Bromophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-methyl-5-naphth-2-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(3-Chlorothien-2-yl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,Methyl3-(1-ethyl-3-methyl-8-oxo-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)propanoate,5-(4-Chlorophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(4-Aminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(4-fluorophenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(3-Bromophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Methyl-5-phenyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-(2-Hydroxyethyl)-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,1-Ethyl-5-(3-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(2-Aminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(2-methoxyphenyl)-3-methyl-6,7-dihydro-1H-yrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-methyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(3-Aminophenyl)-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-5-thione,5-(4-Aminophenyl)-3-tert-butyl-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(4-Aminophenyl)-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(4-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(4-Aminophenyl)-3-methyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Methyl-5-phenyl-1-(2,2,2-trifluoroethyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-Cyclohexyl-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-methyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-tert-Butyl-1-ethyl-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,4-(1-Ethyl-3-isopropyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,5-(2,4-Dimethoxyphenyl)-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-tert-Butyl-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-isopropyl-1-propyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,4-(3-isopropyl-8-oxo-1-propyl-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,5-(2,4-Dimethoxyphenyl)-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3,5-Di-tert-buty-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,4-(3-tert-Butyl-1-ethyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,3-tert-Butyl-5-(2,4-dimethoxyphenyl)-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3,5-Di-tert-butyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-propyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,4-(3-tert-Butyl-8-oxo-1-propyl-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,3-tert-Butyl-5-(2,4-dimethoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,1-Ethyl-3-methyl-5-pyrid-3-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-methyl-5-pyrid-2-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-methyl-5-phenyl-1,6-dihydropyrazolo[4,3-e][1,4]diazepin-8-ylcyanamide,N-[4-(1-Ethyl-3-methyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)phenyl]-(phenylsulphonyl)benzenesulphonamide,1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,1-Cyclopropylmethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Allyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-methyl-5-(4-trifluoromethylphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-isopropyl-5-(4-trifluoromethylphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-(4-trifluoromethylphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-isopropyl-1-propyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,3,5-Di-tert-butyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,5-tert-Butyl-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazapin-8-thione,(±)3-sec-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,(±)3-sec-Butyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,(±)3-sec-Butyl-5-phenyl-1-propyl-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,(±)3-sec-Butyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexyl-1-ethyl-5-phenyl-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexyl-5-phenyl-1-propyl-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexylmethyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexylmethyl-5-phenyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexylmethyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-5-one,3-Cyclohexylmethyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-8-oxo-5-phenyl-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-3-carboxylicacid ethyl ester,5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazapin-8-ylidenecyanamide,1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,1-Ethyl-3-isopropyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,1-Ethyl-5-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,3-isopropyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(4-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,(±)3-sec-Butyl-1-ethyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,(±)3-sec-Butyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-methyl-5-(3,4,-trimethoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(3-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(2-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3,5-diphenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(4-hydroxyphenyl)-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(4-Hydroxyphenyl)-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-(4-hydroxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,or3-Ethoxymethyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one.9. A method of claim 1 wherein said compound is1-Ethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,1-Ethyl-5-(2-methoxyphenyl)-3-methyl-6,7-dihydro-1H-yrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,5-(4-Aminophenyl)-3-tert-butyl-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(4-Aminophenyl)-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(4-hydroxyphenyl)-3-methyl-6,1-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-Cyclohexyl-1-ethyl-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-methyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-tert-Butyl-1-ethyl-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,4-(1-Ethyl-3-isopropyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,5-(2,4-Dimethoxyphenyl)-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-tert-Butyl-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Isopropyl-1-propyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,4-(3-Isopropyl-8-oxo-1-propyl-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,5-(2,4-Dimethoxyphenyl)-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3,5-Di-tert-butyl-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,4-(3-tert-Butyl-1-ethyl-8-oxo-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,3-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,1-Ethyl-3-methyl-5-phenyl-1,6-dihydropyrazolo[4,3-e][1,4]diazepin-8-ylcyanamide,1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,(±)3-sec-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,(±)3-sec-Butyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,(±)3-sec-Butyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexylmethyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,1-Ethyl-3-isopropyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(4-methoxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,3-Isopropyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(4-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,(±)3-sec-Butyl-1-ethyl-5-(4-methoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-methyl-5-(3,4,5-trimethoxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(3-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(2-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3,5-diphenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(4-hydroxyphenyl)-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(4-Hydroxyphenyl)-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-(4-hydroxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,or3-Ethoxymethyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one.10. A method of claim 1 wherein said compound is1-Ethyl-3-methyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,5-(4-Aminophenyl)-3-tert-butyl-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(4-Aminophenyl)-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,4-(1-Ethyl-3-isopropyl-8-oxo-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,5-tert-Butyl-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,4-(3-Isopropyl-8-oxo-1-propyl-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,3,5-Di-tert-butyl-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,4-(3-tert-Butyl-1-ethyl-8-oxo-1,6,7,8-tetrahydropyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,3-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,1-Ethyl-3-methyl-5-phenyl-1,6-dihydropyrazolo[4,3-e][1,4]diazepin-8-ylcyanamide,1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,(±)3-sec-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,(±)3-sec-Butyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,(±)3-sec-Butyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexylmethyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-tert-Butyl-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazapin-8-ylidenecyanamide,1-Ethyl-3-isopropyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide,1-Ethyl-5-(4-hydroxyphenyl)-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,5-(4-Hydroxyphenyl)-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-(4-hydroxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one.11. A method of claim 1 wherein said compound is1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,5-(4-Aminophenyl)-1-ethyl-3-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(4-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,4-(1-Ethyl-3-isopropyl-8-oxo-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitrile,5-tert-Butyl-3-isopropyl-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,4-(3-Isopropyl-8-oxo-1-propyl-1,6,7,8-tetrahydro-pyrazolo[4,3-e][1,4]diazepin-5-yl)benzonitriie,3-tert-Butyl-1-ethyl-5-p-tolyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Butyl-1-ethyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-thione,(±)3-sec-Butyl-1-ethyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,(±)3-sec-Butyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-Cyclohexyl-1-propyl-5-pyrid-4-yl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-5-(4-methoxyphenyl)-1-propyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-5-(2-hydroxyphenyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,3-tert-Butyl-1-ethyl-5-(4-hydroxyphenyl)-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-one,1-Ethyl-3-isopropyl-5-phenyl-6,7-dihydro-1H-pyrazolo[4,3-e][1,4]diazepin-8-ylidenecyanamide.12. A method of claim 1 wherein said (C₅-C₁₀)aryl is phenyl or pyridyl.